N-methylaminomethyl isoindole compounds and compositions comprising and methods of using the same

ABSTRACT

This invention relates to N-methylaminomethyl-isoindoline compounds, and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.

This application claims priority to U.S. Provisional Application No.60/845,227, filed Sep. 15, 2006, the entirety of which is incorporatedherein by reference.

1. FIELD OF THE INVENTION

This invention relates to N-methylaminomethyl isoindole compounds.Pharmaceutical compositions comprising the compounds and methods fortreating, preventing and managing various disorders are also disclosed.

2. BACKGROUND OF THE INVENTION

2.1 Pathobiology of Cancer and Other Diseases

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples includes cancer of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. However, options for thetreatment of cancer are limited. For example, in the case of bloodcancers (e.g., multiple myeloma), few treatment options are available,especially when conventional chemotherapy fails and bone-marrowtransplantation is not an option. A tremendous demand therefore existsfor new methods and compositions that can be used to treat patients withcancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,TNF-α, bFGF).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to: diabetic retinopathy; retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasia;arthritis; and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNF-α, may be useful in thetreatment and prevention of various diseases and conditions.

2.2 Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein andFederman, eds., Chapter 12, Section IV). Recently, cancer therapy couldalso involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient. Additionally, surgery may not completelyremove neoplastic tissue. Radiation therapy is only effective when theneoplastic tissue exhibits a higher sensitivity to radiation than normaltissue. Radiation therapy can also often elicit serious side effects.Hormonal therapy is rarely given as a single agent. Although hormonaltherapy can be effective, it is often used to prevent or delayrecurrence of cancer after other treatments have removed the majority ofcancer cells. Biological therapies and immunotherapies are limited innumber and may produce side effects such as rashes or swellings,flu-like symptoms, including fever, chills and fatigue, digestive tractproblems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly, orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove or become refractory to standard chemotherapeutictreatment protocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443.

Still, there is a significant need for safe and effective methods oftreating, preventing and managing cancer and other diseases andconditions, particularly for diseases that are refractory to standardtreatments, such as surgery, radiation therapy, chemotherapy andhormonal therapy, while reducing or avoiding the toxicities and/or sideeffects associated with the conventional therapies.

3. SUMMARY OF THE INVENTION

This invention is directed, in part, to N-methylaminomethyl isoindolecompounds, and pharmaceutically acceptable salts, solvates (e.g.,hydrates), prodrugs, or stereoisomers thereof.

This invention also encompasses methods of treating and managing variousdiseases or disorders. The methods comprise administering to a patientin need of such treatment or management a therapeutically effectiveamount of a compound of this invention, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof.

The invention also encompasses methods of preventing various diseasesand disorders, which comprise administering to a patient in need of suchprevention a prophylactically effective amount of a compound of thisinvention, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, or prodrug thereof.

This invention also encompasses pharmaceutical compositions, single unitdosage forms, dosing regimens and kits which comprise a compound of thisinvention, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.

4. DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, this invention encompasses N-methylaminomethylisoindole compounds, and pharmaceutically acceptable salts, solvates,stereoisomers and prodrugs thereof.

In another embodiment, this invention encompasses methods of treating,managing, and preventing various diseases and disorders, which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a compound ofthis invention, or a pharmaceutically acceptable salt, solvate,stereoisomer or prodrug thereof. Examples of diseases and disorders aredescribed herein.

In particular embodiments, a compound of this invention, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, is administered in combination with another drug (“secondactive agent”) or treatment. Second active agents include smallmolecules and large molecules (e.g., proteins and antibodies), examplesof which are provided herein, as well as stem cells. Methods, ortherapies, that can be used in combination with the administration ofcompounds of this invention include, but are not limited to, surgery,blood transfusions, immunotherapy, biological therapy, radiationtherapy, and other non-drug based therapies presently used to treat,prevent or manage various disorders described herein.

This invention also encompasses pharmaceutical compositions (e.g.,single unit dosage forms) that can be used in methods disclosed herein.Particular pharmaceutical compositions comprise a compound of thisinvention, or a pharmaceutically acceptable salt, solvate, stereoisomer,or prodrug thereof, and optionally a second active agent.

4.1 Compounds

In one embodiment, this invention encompasses compounds of formula (I):

and pharmaceutically acceptable salts, solvates, stereoisomers, andprodrugs thereof, wherein:

-   denotes chiral center;-   X is CH₂ or C═O;-   R¹ is H, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, (C₂-C₈)alkenyl,    (C₂-C₈)alkynyl, benzyl, aryl, (C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl,    (C₀-C₄)alkyl-(C₂-C₉)heteroaryl, C(O)R³, C(S)R³, C(O)OR⁴,    (C₁-C₈)alkyl-N(R⁶)₂, (C₁-C₈)alkyl-OR⁵, (C₁-C₈)alkyl-C(O)OR⁵,    C(O)NHR³, C(S)NHR³, C(O)NR³R^(3′), C(S)NR³R^(3′) or    (C₁-C₈)alkyl-O(CO)R⁵;-   R² is H, CH₃, or (C₂-C₈)alkyl;-   R³ and R^(3′) are independently

(C₁-C₈)alkyl;

(C₃-C₇)cycloalkyl;

(C₂-C₈)alkenyl;

(C₂-C₈)alkynyl;

benzyl;

(C₀-C₄)alkyl-(C₅-C₁₀)aryl, optionally substituted with one or more of:

-   -   (C₁-C₆)alkyl, said alkyl itself optionally substituted with one        or more halogen,    -   (C₁-C₆)alkoxy, said alkoxy itself optionally substituted with        one or more halogen,    -   SCY₃, wherein Y is hydrogen or halogen,    -   NZ₂, wherein Z is hydrogen or (C₁-C₆)alkyl    -   (C₁-C₆)alkylenedioxy, or    -   halogen;

(C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl;

(C₀-C₄)alkyl-(C₂-C₉)heteroaryl;

(C₀-C₈)alkyl-N(R⁶)₂;

(C₁-C₈)alkyl-OR⁵;

(C₁-C₈)alkyl-C(O)OR⁵;

(C₁-C₈)alkyl-O(CO)R⁵; or

C(O)OR⁵;

-   R⁴ is (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,    (C₁-C₄)alkyl-OR⁵, benzyl, aryl,    (C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl, or    (C₀-C₄)alkyl-(C₂-C₈)heteroaryl;-   R⁵ is (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, benzyl,    (C₅-C₁₀)aryl, or (C₂-C₉)heteroaryl;-   each occurrence of R⁶ is independently H, (C₁-C₈)alkyl,    (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, benzyl, (C₅-C₁₀)aryl,    (C₂-C₈)heteroaryl, or (C₀-C₈)alkyl-C(O)O—R⁵, or    two R⁶ groups can join to form a heterocycloalkyl group.

In one embodiment, X is C═O. In another embodiment, X is CH₂.

In one embodiment, R¹ is H. In another embodiment, R¹ is CH₃. In anotherembodiment, R¹ is (C₂-C₈)alkyl. In another embodiment, R¹ is(C₃-C₇)cycloalkyl. In another embodiment, R¹ is (C₂-C₈)alkenyl. Inanother embodiment, R¹ is (C₂-C₈)alkynyl. In another embodiment, R¹ isbenzyl. In another embodiment, R¹ is aryl. In another embodiment, R¹ is(C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl. In another embodiment, R¹ is(C₀-C₄)alkyl-(C₂-C₉)heteroaryl. In another embodiment, R¹ is C(O)R³. Inanother embodiment, R¹ is C(S)R³. In another embodiment, R¹ is C(O)OR⁴.In another embodiment, R¹ is (C₁-C₈)alkyl-N(R⁶)₂. In another embodiment,R¹ is (C₁-C₈)alkyl-OR⁵. In another embodiment, R¹ is(C₁-C₈)alkyl-C(O)OR⁵. In another embodiment, R¹ is C(O)NHR³. In oneembodiment, R1 is C(O)NH—(C₀-C₄)alkyl-(C₅-C₁₀)aryl, wherein the aryl isoptionally substituted as described herein below. In another embodiment,R¹ is C(S)NHR³. In another embodiment, R¹ is C(O)NR³R^(3′). In anotherembodiment, R¹ is C(S)NR³R^(3′). In another embodiment, R¹is(C₁-C₈)alkyl-O(CO)R⁵.

In one embodiment, R² is H. In another embodiment, R² is (C₁-C₈)alkyl.

In one embodiment, R³ is (C₁-C₈)alkyl. In another embodiment, R³ is(C₃-C₇)cycloalkyl. In another embodiment, R³ is (C₂-C₈)alkenyl. Inanother embodiment, R³ is (C₂-C₈)alkynyl. In another embodiment, R³ isbenzyl. In another embodiment, R³ is (C₀-C₄)alkyl-(C₅-C₁₀)aryl,optionally substituted with one or more of: (C₁-C₆)alkyl, said alkylitself optionally substituted with one or more halogen; (C₁-C₆)alkoxy,said alkoxy itself optionally substituted with one or more halogen;SCY₃, wherein Y is hydrogen or halogen; NZ₂, wherein Z is hydrogen or(C₁-C₆)alkyl; (C₁-C₆)alkylenedioxy; or halogen. In another embodiment,R³ is (C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl. In another embodiment, R³ is(C₀-C₄)alkyl-(C₂-C₉)heteroaryl. In another embodiment, R³ is(C₀-C₈)alkyl-N(R⁶)₂. In another embodiment, R³ is (C₁-C₈)alkyl-OR⁵. Inanother embodiment, R³ is (C₁-C₈)alkyl-C(O)OR⁵. In another embodiment,R³ is (C₁-C₈)alkyl-O(CO)R⁵. In another embodiment, R³ is C(O)OR⁵.

In one embodiment, R^(3′) is (C₁-C₈)alkyl. In another embodiment, R^(3′)is (C₃-C₇)cycloalkyl. In another embodiment, R^(3′) is (C₂-C₈)alkenyl.In another embodiment, R^(3′) is (C₂-C₈)alkynyl. In another embodiment,R^(3′) is benzyl. In another embodiment, R^(3′) is aryl. In anotherembodiment, R^(3′) is (C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl. In anotherembodiment, R^(3′) is (C₀-C₄)alkyl-(C₂-C₉)heteroaryl. In anotherembodiment, R^(3′) is (C₀-C₈)alkyl-N(R⁶)₂. In another embodiment, R^(3′)is (C₁-C₈)alkyl-OR⁵. In another embodiment, R^(3′) is(C₁-C₈)alkyl-C(O)R⁵. In another embodiment, R^(3′) is(C₁-C₈)alkyl-O(CO)R⁵. In another embodiment, R^(3′) is C(O)OR⁵.

In one embodiment, R⁴ is (C₁-C₈)alkyl. In another embodiment, R⁴ is(C₂-C₈)alkenyl. In another embodiment, R⁴ is (C₂-C₈)alkynyl. In anotherembodiment, R⁴ is (C₁-C₄)alkyl-OR⁵. In another embodiment, R⁴ is benzyl.In another embodiment, R⁴ is aryl. In another embodiment, R⁴ is(C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl. In another embodiment, R⁴ is(C₀-C₄)alkyl-(C₂-C₉)heteroaryl.

In one embodiment, R⁵ is (C₁-C₈)alkyl. In another embodiment, R⁵ is(C₂-C₈)alkenyl. In another embodiment, R⁵ is (C₂-C₈)alkynyl. In anotherembodiment, R⁵ is benzyl. In another embodiment, R⁵ is (C₅-C₁₀)aryl. Inanother embodiment, R⁵ is (C₂-C₉)heteroaryl.

In one embodiment, R⁶ is H. In another embodiment, R⁶ is (C₁-C₈)alkyl.In another embodiment, R⁶ is (C₂-C₈)alkenyl. In another embodiment, R⁶is (C₂-C₈)alkynyl. In another embodiment, R⁶ is benzyl. In anotherembodiment, R⁶ is (C₅-C₁₀)aryl. In another embodiment, R⁶ is(C₂-C₉)heteroaryl. In another embodiment, R⁶ is or(C₀-C₈)alkyl-C(O)O—R⁵. In another embodiment, two R⁶ groups join to forma heterocycloalkyl group.

In other embodiments, this invention encompasses any combination of X,R¹, R², R³, R^(3′), R⁴, R⁵, and/or R⁶ as set forth above.

In one embodiment, this invention encompasses compounds of formula (II):

and pharmaceutically acceptable salts, solvates, stereoisomers, andprodrugs thereof, wherein:

-   * denotes chiral center;-   X is CH₂ or C═O;-   R is (C₁-C₆)alkyl; (C₁-C₆)alkoxy; amino; (C₁-C₆)alkyl-amino;    dialkylamino, wherein each of the alkyl groups is independently    (C₁-C₆)alkyl; (C₀-C₄)alkyl-(C₆-C₁₀)aryl, optionally substituted with    one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen; 5 to 10 membered    heteroaryl, optionally substituted with one or more (C₁-C₆)alkyl;    —NHR′; or (C₀-C₈)alkyl-N(R″)₂;-   R¹ is: (C₁-C₆)alkyl;

(C₀-C₄)alkyl-(C₆-C₁₀)aryl, optionally substituted with one or more of:

-   -   (C₁-C₆)alkyl, said alkyl itself optionally substituted with one        or more halogen,    -   (C₁-C₆)alkoxy, said alkoxy itself optionally substituted with        one or more halogen,    -   (C₁-C₆)alkylenedioxy, or    -   halogen; or

5 to 10 membered heteroaryl, optionally substituted with one or more(C₁-C₆)alkyl; and each occurrence of R″ is independently H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, benzyl, (C₆-C₁₀)aryl, 5 to10 membered heteroaryl, or (C₀-C₈)alkyl-C(O)O—(C₁-C₈)alkyl.

In one embodiment, X is C═O. In another embodiment, X is CH₂.

In one embodiment, R is (C₁-C₆)alkyl. In certain specific embodiments, Ris methyl, ethyl, propyl, cyclopropyl, or hexyl.

In another embodiment, R is (C₁-C₆)alkoxy. In certain specificembodiments, R is t-butoxy.

In another embodiment, R is amino. In another embodiment, R is(C₁-C₆)alkyl-amino. In another embodiment, R is dialkylamino, whereineach of the alkyl groups is independently (C₁-C₆)alkyl. In certainspecific embodiments, R is dimethylamino.

In another embodiment, R is (C₀-C₄)alkyl-(C₆-C₁₀)aryl, optionallysubstituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halogen. Incertain specific embodiments, R is phenyl or —CH₂-phenyl, optionallysubstituted with one or more methyl and/or halogen.

In another embodiment, R is 5 to 10 membered heteroaryl, optionallysubstituted with one or more (C₁-C₆)alkyl. In certain specificembodiments, R is pyridyl or furanyl.

In another embodiment, R is —NHR′.

In one embodiment, R′ is (C₁-C₆)alkyl, optionally substituted with oneor more halogen. In certain specific embodiments, R′ is methyl, ethyl,propyl, t-butyl, cyclohexyl, or trifluoromethyl.

In another embodiment, R′ is (C₀-C₄)alkyl-(C₆-C₁₀)aryl, optionallysubstituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkylenedioxy or halogen. In certain specific embodiments, R′ isphenyl, optionally substituted with one or more of methyl, methoxy,and/or chloride. In another embodiment, R′ is naphthyl. In anotherembodiment, R′ is phenyl, substituted with (C₁-C₆)alkylenedioxy,specifically, methylenedioxy. In another embodiment, R′ is toluoyl.

In another embodiment, R′ is 5 to 10 membered heteroaryl, optionallysubstituted with one or more (C₁-C₆)alkyl. In certain specificembodiments, R′ is pyridyl or naphthyl.

In one embodiment, R is (C₀-C₈)alkyl-N(R″)₂.

In another embodiment, R″ is H. In another embodiment, R″ is(C₁-C₈)alkyl. In another embodiment, R″ is (C₂-C₈)alkenyl. In anotherembodiment, R″ is (C₂-C₈)alkynyl. In another embodiment, R″ is benzyl.In another embodiment, R″ is (C₆-C₁₀)aryl. In another embodiment, R″ is5 to 10 membered heteroaryl. In another embodiment, R″ is(C₀-C₈)alkyl-C(O)O—(C₁-C₈)alkyl. In a specific embodiment, one of R″ isH and the other of R″ is (C₀-C₈)alkyl-C(O)O—(C₁-C₈)alkyl, in particular,—COO-isobutyl.

In other embodiments, this invention encompasses any combination of X,R, and/or R′ as set forth above.

Examples include, but are not limited to, those listed below, or apharmaceutically acceptable salt, solvate (e.g., hydrate), orstereoisomer thereof:

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salt” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids such as, but not limited to, acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic,glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, propionic, phosphoric, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like.Suitable are hydrochloric, hydrobromic, phosphoric, and sulfuric acids.

As used herein, and unless otherwise specified, the term “solvate” meansa compound provided herein or a salt thereof that further includes astoichiometric or non-stoichiometric amount of solvent bound bynon-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein, and unless otherwise specified, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,compounds that comprise biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Other examples of prodrugs include compounds thatcomprise —NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically beprepared using well-known methods, such as those described in Burger'sMedicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E.Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed.,Elselvier, New York 1985).

As used herein, and unless otherwise specified, the terms“biohydrolyzable carbamate,” “biohydrolyzable carbonate,”“biohydrolyzable ureide” and “biohydrolyzable phosphate” mean acarbamate, carbonate, ureide and phosphate, respectively, of a compoundthat either: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically inactive but is converted in vivo to the biologicallyactive compound. Examples of biohydrolyzable carbamates include, but arenot limited to, lower alkylamines, substituted ethylenediamines,aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines,and polyether amines.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, morepreferably greater than about 90% by weight of one stereoisomer of thecompound and less than about 10% by weight of the other stereoisomers ofthe compound, even more preferably greater than about 95% by weight ofone stereoisomer of the compound and less than about 5% by weight of theother stereoisomers of the compound, and most preferably greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, preferably greater than about70% by weight, more preferably greater than about 80% by weight of onestereoisomer of a compound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center (e.g., >97% eee). Similarly, the term“enantiomerically enriched” means a stereomerically enriched compositionof a compound having one chiral center.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a saturated straight chain or branched hydrocarbon having number ofcarbon atoms as specified herein. Representative saturated straightchain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl,and -n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, and the like. The term “alkyl” also encompassescycloalkyl.

As used herein, and unless otherwise specified, the term “cycloalkyl”means a specie of alkyl containing from 3 to 15 carbon atoms, withoutalternating or resonating double bonds between carbon atoms. It maycontain from 1 to 4 rings. Examples of unsubstituted cycloalkylsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and adamantyl. A cycloalkyl may be substituted with one ormore of the substituents as defined below.

As used herein, and unless otherwise specified, the term “alkenyl” meansa straight chain or branched hydrocarbon having from 2 to 20 carbonatoms, specifically 2-10 carbon atoms, more specifically 2-6 carbonatoms, and including at least one carbon-carbon double bond.Representative straight chain and branched (C₂-C₁₀)alkenyls includevinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl,2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl,2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl,2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, and 3-decenyl. The doublebond of an alkenyl group may be unconjugated or conjugated to anotherunsaturated group. An alkenyl group may be unsubstituted or substituted.

As used herein, and unless otherwise specified, the term “alkynyl” meansa straight chain or branched non-cyclic hydrocarbon having from 2 to 20carbon atoms, specifically 2-10 carbon atoms, more specifically 2-6carbon atoms, and including at lease one carbon-carbon triple bond.Representative straight chain and branched-(C₂-C₁₀)alkynyls includeacetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl,1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl,1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, andthe like. The triple bond of an alkynyl group may be unconjugated orconjugated to another unsaturated group. An alkynyl group may beunsubstituted or substituted.

As used herein, and unless otherwise specified, the term “alkoxy” refersto —O-(alkyl), wherein alkyl is defined herein. Examples of alkoxyinclude, but are not limited to, —OCH₃, —OCH₂CH₃, —O(CH₂)₂CH₃,—O(CH₂)₃CH₃, —O(CH₂)₄CH₃, —O(CH₂)₅CH₃, —O-cyclopropyl, —O-isobutyl, andthe like.

As used herein, the term “aryl” means a carbocyclic aromatic ringcontaining from 5 to 14 ring atoms. The ring atoms of a carbocyclic arylgroup are all carbon atoms. Aryl ring structures include compoundshaving one or more ring structures such as mono-, bi-, or tricycliccompounds as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl and the like. Specifically, the aryl group isa monocyclic ring or bicyclic ring. Representative aryl groups includephenyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl andnaphthyl.

As used herein, and unless otherwise specified, the term “heteroaryl”means an aromatic ring containing from 5 to 14 ring atoms, of which atleast one (e.g., one, two, or three) is a heteroatom (e.g., nitrogen,oxygen, or sulfur). Heteroaryl ring structures include compounds havingone or more ring structures such as mono-, bi-, or tricyclic compounds,as well as fused heterocyclic moieties. Examples of heteroaryls include,but are not limited to, triazolyl, tetrazolyl, oxadiazolyl, pyridyl,furyl, benzofuranyl, thiophenyl, thiazolyl, benzothiophenyl,benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, puridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, quinazolinyl, benzoquinazolinyl, quinoxalinyl, acridinyl,pyrimidyl, oxazolyl, benzo[1,3]dioxole and2,3-dihydro-benzo[1,4]dioxine.

As used herein, and unless otherwise specified, the term“heterocycloalkyl” refers to a cycloalkyl group in which at least one ofthe carbon atoms in the ring is replaced by a heteroatom (e.g., O, S orN), such as, but not limited to, morpholino or piperidinyl.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

4.2 Methods of Treatment, Prevention and Management

This invention encompasses methods of treating, preventing, and/ormanaging various diseases or disorders using a compound of thisinvention, or a pharmaceutically acceptable salt, solvate, stereoisomeror prodrug thereof. Without being limited by a particular theory,compounds provided herein can control angiogenesis or inhibit theproduction of certain cytokines including, but not limited to, TNF-α,IL-1β, IL-12, IL-18, GM-CSF, and/or IL-6. Without being limited by aparticular theory, compounds provided herein can stimulate theproduction of certain other cytokines including IL-10, and also act as acostimulatory signal for T cell activation, resulting in increasedproduction of cytokines such as, but not limited to, IL-12 and/or IFN-γ.In addition, compounds provided herein can enhance the effects of NKcells and antibody-mediated cellular cytotoxicity (ADCC). Further,compounds provided herein may be immunomodulatory and/or cytotoxic, andthus, may be useful as chemotherapeutic agents. Consequently, withoutbeing limited by a particular theory, some or all of suchcharacteristics possessed by the compounds provided herein may renderthem useful in treating, managing, and/or preventing various diseases ordisorders.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including ComplexRegional Pain Syndrome (“CRPS”), Macular Degeneration (“MD”) and relatedsyndromes, skin diseases, pulmonary disorders, asbestos-relateddisorders, parasitic diseases, immunodeficiency disorders, CNSdisorders, CNS injury, atherosclerosis and related disorders,dysfunctional sleep and related disorders, hemoglobinopathy and relateddisorders (e.g., anemia), TNFα and other cytokines related disorders,and other various diseases and disorders.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic or therapeutic agent do not result in a cureof the disease or disorder.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in PCT/US04/14004, filed May 5, 2004. All ofthese references are incorporated herein in their entireties byreference.

Specific examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are particularly useful for treating cancers of the blood andbone marrow, such as multiple myeloma and acute and chronic leukemias,for example, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds of the invention can be used for treating,preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesotheliooma syndrome, peritoneal carcinoma, papillary serouscarcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma,cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation.

In one specific embodiment, this invention encompasses methods oftreating, preventing or managing various forms of leukemias such aschronic lymphocytic leukemia, chronic myelocytic leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia and acutemyeloblastic leukemia, including leukemias that are relapsed, refractoryor resistant, as disclosed in U.S. publication no. 2006/0030594,published Feb. 9, 2006, which is incorporated in its entirety byreference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another specific embodiment, this invention encompasses methods oftreating, preventing or managing various types of lymphomas, includingNon-Hodgkin's lymphoma (NHL). The term “lymphoma” refers a heterogenousgroup of neoplasms arising in the reticuloendothelial and lymphaticsystems. “NHL” refers to malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract. Examples of NHL include, butare not limited to, mantle cell lymphoma, MCL, lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma, ILL,diffuse poorly differentiated lymphocytic lymphoma, PDL, centrocyticlymphoma, diffuse small-cleaved cell lymphoma, DSCCL, follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mentle zonelymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, endometriosis, Crohn'sdisease, heart failure, advanced heart failure, renal impairment,endotoxemia, toxic shock syndrome, osteoarthritis, retrovirusreplication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Examples of pain include, but are not limited to those described in U.S.patent publication no. 2005/0203142, published Sep. 15, 2005, which isincorporated herein by reference. Specific types of pain include, butare not limited to, nociceptive pain, neuropathic pain, mixed pain ofnociceptive and neuropathic pain, visceral pain, migraine, headache andpost-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS typeI, CRPS type II, reflex sympathetic dystrophy (RSD), reflexneurovascular dystrophy, reflex dystrophy, sympathetically maintainedpain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy,shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia,post herpetic neuralgia, cancer related pain, phantom limb pain,fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, centralpost-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain,luetic neuropathy, and other painful neuropathic conditions such asthose induced by drugs such as vincristine and velcade.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004, which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, keratoses and related symptoms, skindiseases or disorders characterized with overgrowths of the epidermis,acne, and wrinkles.

As used herein, the term “keratosis” refers to any lesion on theepidermis marked by the presence of circumscribed overgrowths of thehorny layer, including but not limited to actinic keratosis, seborrheickeratosis, keratoacanthoma, keratosis follicularis (Darier disease),inverted follicular keratosis, palmoplantar keratoderma (PPK, keratosispalmaris et plantaris), keratosis pilaris, and stucco keratosis. Theterm “actinic keratosis” also refers to senile keratosis, keratosissenilis, verruca senilis, plana senilis, solar keratosis, keratoderma orkeratoma. The term “seborrheic keratosis” also refers to seborrheicwart, senile wart, or basal cell papilloma. Keratosis is characterizedby one or more of the following symptoms: rough appearing, scaly,erythematous papules, plaques, spicules or nodules on exposed surfaces(e.g., face, hands, ears, neck, legs and thorax), excrescences ofkeratin referred to as cutaneous horns, hyperkeratosis, telangiectasias,elastosis, pigmented lentigines, acanthosis, parakeratosis,dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,cellular atypia, mitotic figures, abnormal cell-cell adhesion, denseinflammatory infiltrates and small prevalence of squamous cellcarcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratoses, sign of Leser-Trelat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A1, published Oct. 27,2005, which is incorporated herein by reference. Specific examplesinclude pulmonary hypertension and related disorders. Examples ofpulmonary hypertension and related disorders include, but are notlimited to: primary pulmonary hypertension (PPH); secondary pulmonaryhypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonaryhypertension; pulmonary arterial hypertension (PAH); pulmonary arteryhypertension; idiopathic pulmonary hypertension; thrombotic pulmonaryarteriopathy (TPA); plexogenic pulmonary arteriopathy; functionalclasses I to IV pulmonary hypertension; and pulmonary hypertensionassociated with, related to, or secondary to, left ventriculardysfunction, mitral valvular disease, constrictive pericarditis, aorticstenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonaryvenous drainage, pulmonary venoocclusive disease, collagen vasulardisease, congenital heart disease, HIV virus infection, drugs and toxinssuch as fenfluramines, congenital heart disease, pulmonary venoushypertension, chronic obstructive pulmonary disease, interstitial lungdisease, sleep-disordered breathing, alveolar hypoventilation disorder,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorder, chronic thromboemboli, connective tissue disease, lupusincluding systemic and cutaneous lupus, schistosomiasis, sarcoidosis orpulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, mesothelioma, asbestosis, malignantpleural effusion, benign exudative effusion, pleural plaques, pleuralcalcification, diffuse pleural thickening, rounded atelectasis, fibroticmasses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. application Ser. No. 11/271,963, filed Nov. 14, 2005,which is incorporated herein by reference. Parasitic diseases includediseases and disorders caused by human intracellular parasites such as,but not limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L.donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana,L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C.parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S.haematobium, Trypanosoma ssp., Toxoplasma ssp., and O. volvulus. Otherdiseases and disorders caused by non-human intracellular parasites suchas, but not limited to, Babesia bovis, Babesia canis, Banesia Gibsoni,Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp., andTheileria ssp., are also encompassed. Specific examples include, but arenot limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis,toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. application Ser. No. 11/289,723, filed Nov. 30,2005. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-tenlangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulineinia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344A1, published Jun. 30,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, include, but are not limited to,Amyotrophic Lateral Sclerosis, Alzheimer Disease, Parkinson Disease,Huntington's Disease, Multiple Sclerosis other neuroimmunologicaldisorders such as Tourette Syndrome, delerium, or disturbances inconsciousness that occur over a short period of time, and amnesticdisorder, or discreet memory impairments that occur in the absence ofother central nervous system impairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. application Ser. No. 11/284,403,filed Nov. 18, 2005, which is incorporated herein by reference. Specificexamples include, but are not limited to, CNS injury/damage and relatedsyndromes, include, but are not limited to, primary brain injury,secondary brain injury, traumatic brain injury, focal brain injury,diffuse axonal injury, head injury, concussion, post-concussionsyndrome, cerebral contusion and laceration, subdural hematoma,epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI,central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome,conus medullaris syndrome, cauda equina syndrome, neurogenic shock,spinal shock, altered level of consciousness, headache, nausea, emesis,memory loss, dizziness, diplopia, blurred vision, emotional lability,sleep disturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but not limited to, viral, genetic,allergic, and autoimmune diseases. Specific examples include, but notlimited to, HIV, hepatitis, adult respiratory distress syndrome, boneresorption diseases, chronic pulmonary inflammatory diseases,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft versus hostdisease, graft rejection, auto-immune disease, rheumatoid spondylitis,Crohn's disease, ulcerative colitis, inflammatory-bowel disease,multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy,radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated herein by reference.Specific examples include, but are not limited to, all forms ofconditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated by theinvention including diseases of the cardiovascular and renal system,such as, but not limited to, renal angioplasty, percutaneous coronaryintervention (PCI), percutaneous transluminal coronary angioplasty(PTCA), carotid percutaneous transluminal angioplasty (PTA), coronaryby-pass grafting, angioplasty with stent implantation, peripheralpercutaneous transluminal intervention of the iliac, femoral orpopliteal arteries, and surgical intervention using impregnatedartificial grafts. The following chart provides a listing of the majorsystemic arteries that may be in need of treatment, all of which arecontemplated by the invention:

Artery Body Area Supplied Axillary Shoulder and axilla Brachial Upperarm Brachiocephalic Head, neck, and arm Celiac Divides into leftgastric, splenic, and hepatic arteries Common carotid Neck Common iliacDivides into external and internal iliac arteries Coronary Heart Deepfemoral Thigh Digital Fingers Dorsalis pedis Foot External carotid Neckand external head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks muscles, uterus and vagina Leftgastric Esophagus and stomach Middle sacral Sacrum Ovarian OvariesPalmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial CalfPulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach, pancreas,and spleen Subclavian Shoulder Superior mesenteric Pancreas, smallintestine, ascending and transverse colon Testicular Testes UlnarForearm

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα and other cytokines related disorders include, but arenot limited to, those described in WO 98/03502 and WO 98/54170, both ofwhich are incorporated herein in their entireties by reference. Specificexamples include, but are not limited to: endotoxemia or toxic shocksyndrome; cachexia; adult respiratory distress syndrome; bone resorptiondiseases such as arthritis; hypercalcemia; Graft versus Host Reaction;cerebral malaria; inflammation; tumor growth; chronic pulmonaryinflammatory diseases; reperfusion injury; myocardial infarction;stroke; circulatory shock; rheumatoid arthritis; Crohn's disease; HIVinfection and AIDS; other disorders such as rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis and other arthritic conditions,septic shock, septis, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; cAMP related disorders such as septicshock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome,post ischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

In other embodiments, the use of compounds of this invention in variousimmunological applications, in particular, as vaccine adjuvants,particularly anticancer vaccine adjuvants, as disclosed in U.S.Provisional Application No. 60/712,823, filed Sep. 1, 2005, which isincorporated herein in its entirety by reference, is also encompassed.This aspect of the invention also relates to the uses of compounds ofthis invention in combination with vaccines to treat or prevent canceror infectious diseases, and other various uses of immunomodulatorycompounds such as reduction or desensitization of allergic reactions.

Doses of a compound of this invention, or a pharmaceutically acceptablesalt, solvate, stereoisomer or prodrug thereof, vary depending onfactors such as: specific indication to be treated, prevented, ormanaged; age and condition of a patient; and amount of second activeagent used, if any. Generally, a compound of this invention, or apharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, may be used in an amount of from about 0.1 mg to about 500 mgper day, and can be adjusted in a conventional fashion (e.g., the sameamount administered each day of the treatment, prevention or managementperiod), in cycles (e.g., one week on, one week off), or in an amountthat increases or decreases over the course of treatment, prevention, ormanagement. In other embodiments, the dose can be from about 1 mg toabout 300 ing, from about 0.1 mg to about 150 mg, from about 1 mg toabout 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg toabout 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about50 mg, from about 20 mg to about 30 mg, from about 10 mg to about 25 mg,or from about 1 mg to about 20 mg.

4.3 Second Active Agents

A compound of this invention, or a pharmaceutically acceptable salt,solvate, stereoisomer or prodrug thereof, can be combined with otherpharmacologically active compounds (“second active agents”) in methodsand compositions of the invention. It is believed that certaincombinations may work synergistically in the treatment of particulartypes diseases or disorders, and conditions and symptoms associated withsuch diseases or disorders. A compound of this invention, or apharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, can also work to alleviate adverse effects associated withcertain second active agents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions of the invention. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40,Herceptin, rituximab); histone deacetylyase inhibitors (such as, forexample, SAHA and LAQ 824); heat-shock protein-90 inhibitors (such as,for example, 17-AAG); insulin-like growth factor-1 receptor kinaseinhibitors; vascular endothelial growth factor receptor kinaseinhibitors (such as, for example, PTK787); insulin growth factorreceptor inhibitors; lysophosphatidic acid acyltransrerase inhibitors;IkB kinase inhibitors; p38MAPK inhibitors; EGFR inhibitors (such as, forexample, gefitinib and erlotinib HCL); HER-2 antibodies (such as, forexample, trastuzumab (Herceptin®) and pertuzumab (Omnitarg™)); VEGFRantibodies (such as, for example, bevacizumab (Avastin™)); VEGFRinhibitors (such as, for example, flk-1 specific kinase inhibitors,SU5416 and ptk787/zk222584); PI3K inhibitors (such as, for example,wortmannin); C-Met inhibitors (such as, for example, PHA-665752);monoclonal antibodies (such as, for example, rituximab (Rituxan®),tositumomab (Bexxar®), edrecolomab (Panorex®) and G250); and anti-TNF-αantibodies. Examples of small molecule active agents include, but arenot limited to, small molecule anti-cancer agents and antibiotics (e.g.,clarithromycin).

Specific second active compounds that can be combined with compounds ofthis invention vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapainmil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstin; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexin; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofuran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

Similarly, examples of specific second agents according to theindications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. applicationSer. Nos. 10/411,649, 10/483,213, 10/411,656, 10/693,794, 10/699,154,and 10/981,189; and U.S. provisional application Nos. 60/554,923,60/565,172, 60/626,975, 60/630,599, 60/631,870, and 60/533,862.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenyloin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), nefazodone (Serzone®),venlafaxine (Effexor®), trazodone (Desyrel®), bupropion (Wellbutrin®),mexiletine, nifedipine, propranolol, tramadol, lamotrigine, ziconotide,ketamine, dextromethorphan, benzodiazepines, baclofen, tizanidine andphenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of MD and related syndromes include, butare not limited to, a steroid, a light sensitizer, an integrin, anantioxidant, an interferon, a xanthine derivative, a growth hormone, aneutrotrophic factor, a regulator of neovascularization, an anti-VEGFantibody, a prostaglandin, an antibiotic, a phytoestrogen, ananti-inflammatory compound or an antiangiogenesis compound, or acombination thereof. Specific examples include, but are not limited to,verteporfin, purlytin, an angiostatic steroid, rhuFab, interferon-2α,pentoxifylline, tin etiopurpurin, motexafin lutetium,9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and itsderivatives, rifamycin and its derivatives, macrolides, metronidazole(U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein, genistin, 6′-O-Malgenistin, 6′-O-Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O-Acdaidzin, glycitein, glycitin, 6′-O-Mal glycitin, biochanin A,formononetin (U.S. Pat. No. 6,001,368), triamcinolone acetomide,dexamethasone (U.S. Pat. No. 5,770,589), thalidomide, glutathione (U.S.Pat. No. 5,632,984), basic fibroblast growth factor (bFGF), transforminggrowth factor b (TGF-b), brain-derived neurotrophic factor (BDNF),plasminogen activator factor type 2 (PAI-2), EYE101 (EyetechPharmaceuticals), LY333531 (Eli Lilly), Miravant, and RETISERT implant(Bausch & Lomb). All of the references cited above are incorporatedherein in their entireties by reference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, and immunomodulatory agents.Specific examples include, but are not limited to, 5-fluorouracil,masoprocol, trichloroacetic acid, salicylic acid, lactic acid, ammoniumlactate, urea, tretinoin, isotretinoin, antibiotics, collagen, botulinumtoxin, interferon, corticosteroid, transretinoic acid and collagens suchas human placental collagen, animal placental collagen, Dermalogen,AlloDerm, Fascia, Cyinetra, Autologen, Zyderm, Zyplast, Resoplast, andIsolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hepertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin I2 (PGI2), epoprostenol (EPO, Floran®, treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin,tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®),irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine,iloprost, betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agent,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenictrioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstiboglucuronate), interfereon gamma, itraconazole, a combination ofdead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, clarithromycin, tetracycline,penicillin, cephalosporins, streptomycin, kanamycin, and erythromycin;antivirals such as, but not limited to, amantadine, rimantadine,acyclovir, and ribavirin; immunoglobulin; plasma; immunologic enhancingdrugs such as, but not limited to, levami sole and isoprinosine;biologics such as, but not limited to, gammaglobulin, transfer factor,interleukins, and interferons; hormones such as, but not limited to,thymic; and other immunologic agents such as, but not limited to, B cellstimulators (e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5),growth factors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: a dopamine agonist or antagonist, such as, but not limitedto, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, pheneizine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine saliclate,physostigmine sulfate, physostigmine bromide, meostigmine bromide,neostigmine methylsulfate, ambenonim chloride, edrophonium chloride,tacrine, pralidoxine chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolinetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betainethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, proinethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, inetopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprises1-threo-methylphenidate, d-threo-methylphendate,dl-threo-methylphenidate, l-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, pheneizine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxine chloride, obidoxine chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betainethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-11 (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; HEMOXIN™ (NIPRISAN™; see U.S. Pat. No. 5,800,819); Gardos channelantagonists such as clotrimazole and triaryl methane derivatives;Deferoxamine; protein C; and transfusions of blood, or of a bloodsubstitute such as Hemospan™ or Hemospan™ PS (Sangart).

Administration of a compound of this invention, or a pharmaceuticallyacceptable salt, solvate, stereoisomer or prodrug thereof, and thesecond active agents to a patient can occur simultaneously orsequentially by the same or different routes of administration. Thesuitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. A preferredroute of administration for compounds of this invention is oral.Preferred routes of administration for the second active agents oringredients of the invention are known to those of ordinary skill in theart. See, e.g., Physicians' Desk Reference, 1755-1760 (56th ed., 2002).

In one embodiment of the invention, the second active agent isadministered intravenously or subcutaneously and once or twice daily inan amount of from about 1 to about 1000 mg, from about 5 to about 500mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. Thespecific amount of the second active agent will depend on the specificagent used, the type of disease being treated or managed, the severityand stage of disease, and the amount(s) of compounds of the inventionand any optional additional active agents concurrently administered tothe patient.

As discussed elsewhere herein, the invention encompasses a method ofreducing, treating and/or preventing adverse or undesired effectsassociated with conventional therapy including, but not limited to,surgery, chemotherapy, radiation therapy, hormonal therapy, biologicaltherapy and immunotherapy. Compounds of the invention and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

4.4 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents of theinvention are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest for a period of time, and repeating this sequentialadministration. Cycling therapy can reduce the development of resistanceto one or more of the therapies, avoid or reduce the side effects of oneof the therapies, and/or improves the efficacy of the treatment.

Consequently, in one specific embodiment of the invention, a compound ofthe invention is administered daily in a single or divided doses in afour to six week cycle with a rest period of about a week or two weeks.The invention further allows the frequency, number, and length of dosingcycles to be increased. Thus, another specific embodiment of theinvention encompasses the administration of a compound of the inventionfor more cycles than are typical when it is administered alone. In yetanother specific embodiment of the invention, a compound of theinvention is administered for a greater number of cycles that wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, a compound of the invention is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 ing toabout 500 mg per day, followed by a break of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.11 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.11 mg to about 50 mg, from about 1 mgto about 50 mg, from about 10 mg to about 50 mg, from about 20 mg toabout 30 mg, or from about 1 mg to about 20 mg, followed by a break.

In one embodiment of the invention, a compound of the invention and asecond active ingredient are administered orally, with administration ofthe compound of the invention occurring 30 to 60 minutes prior to thesecond active ingredient, during a cycle of four to six weeks. Inanother embodiment of the invention, the combination of a compound ofthe invention and a second active ingredient is administered byintravenous infusion over about 90 minutes every cycle.

Typically, the number of cycles during which the combinatorial treatmentis administered to a patient will be from about one to about 24 cycles,more typically from about two to about 16 cycles, and even moretypically from about four to about three cycles.

4.5 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms of the invention comprise a compound of the invention, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof. Pharmaceutical compositions and dosage forms of the inventioncan further comprise one or more excipients.

Pharmaceutical compositions and dosage forms of the invention can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are disclosed in Section 4.3,above.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of a disease may contain larger amounts of one ormore of the active ingredients it comprises than a dosage form used inthe chronic treatment of the same disease. Similarly, a parenteraldosage form may contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease. These and other ways in which specific dosage forms encompassedby this invention will vary from one another will be readily apparent tothose skilled in the art. See, e.g., Remington's PharmaceuticalSciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient may also depend on the specific active ingredientsin the dosage form. For example, the decomposition of some activeingredients may be accelerated by some excipients such as lactose, orwhen exposed to water. Active ingredients that comprise primary orsecondary amines are particularly susceptible to such accelerateddecomposition. Consequently, this invention encompasses pharmaceuticalcompositions and dosage forms that contain little, if any, lactose othermono- or di-saccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositionscomprise active ingredients, a binder/filler, and a lubricant inpharmaceutically compatible and pharmaceutically acceptable amounts.Preferred lactose-free dosage forms comprise active ingredients,microcrystalline cellulose, pre-gelatinized starch, and magnesiumstearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability. Priniciples &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers. Likethe amounts and types of excipients, the amounts and specific types ofactive ingredients in a dosage form may differ depending on factors suchas, but not limited to, the route by which it is to be administered topatients. However, typical dosage forms of the invention comprise acompound of the invention in an amount of from about 0.10 to about 500mg. Typical dosage forms comprise a compound of the invention in anamount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100,150, 200, 250, 300, 350, 400, 450, or 500 mg.

Typical dosage forms comprise the second active ingredient in an amountof I to about 1000 ing, from about 5 to about 500 mg, from about 10 toabout 350 mg, or from about 50 to about 200 mg. Of course, the specificamount of the second active agent will depend on the specific agentused, the type of cancer being treated or managed, and the amount(s) ofa compound of the invention and any optional additional active agentsconcurrently administered to the patient.

4.5.1 Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

A solid oral dosage form of the invention comprises a compound of theinvention, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

4.5.2 Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.5.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention. For example, cyclodextrin andits derivatives can be used to increase the solubility of animmunomodulatory compound of the invention and its derivatives. See,e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

4.5.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms of the invention include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedby this invention are well known to those skilled in the pharmaceuticalarts, and depend on the particular tissue to which a givenpharmaceutical composition or dosage form will be applied. With thatfact in mind, typical excipients include, but are not limited to, water,acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,isopropyl myristate, isopropyl palmitate, mineral oil, and mixturesthereof to form solutions, emulsions or gels, which are non-toxic andpharmaceutically acceptable. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms if desired.Examples of such additional ingredients are well known in the art. See,e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., MackPublishing, Easton Pa. (1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

4.6 Kits

In one embodiment, active ingredients of the invention are preferablynot administered to a patient at the same time or by the same route ofadministration. This invention therefore encompasses kits which, whenused by the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a patient.

A kit of the invention comprises a dosage form of a compound of theinvention. Kits encompassed by this invention can further compriseadditional active ingredients such as oblimersen (Genasense®),melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan,taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin,dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13cis-retinoic acid, or a pharmacologically active mutant or derivativethereof, or a combination thereof. Examples of the additional activeingredients include, but are not limited to, those disclosed herein(see, e.g., section 4.3).

Kits of the invention can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits of the invention can further comprise cells or blood fortransplantation as well as pharmaceutically acceptable vehicles that canbe used to administer one or more active ingredients. For example, if anactive ingredient is provided in a solid form that must be reconstitutedfor parenteral administration, the kit can comprise a sealed containerof a suitable vehicle in which the active ingredient can be dissolved toform a particulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

5. EXAMPLES

Certain embodiments of the invention are illustrated by the followingnon-limiting examples.

5.1[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamicacid T-butyl ester

5.1.1 3-Methyl-phthalic Acid Dimethyl Ester

A stirred mixture of 3-methylphthalic anhydride (10.0 g, 61.7 mmol) inmethanol (90 mL) was heated to reflux for 1 hour. The mixture wasallowed to cool to room temperature and concentrated to give 13 g of thehalf ester. Methyl iodide (18.7 g, 131.5 mmol) was added to a stirredsuspension of half ester (13 g) and sodium bicarbonate (13.0 g, 154.2mmol) in DMF (75 mL). The resulting mixture was stirred at 75° C. oilbath for 1.5 hours. The mixture was cooled to room temperature andpoured into ice water (350 mL). The mixture was extracted with EtOAc(4×80 mL), and the combined EtOAc extracts were washed with water (3×50mL) and brine (50 mL), and dried (MgSO₄). Solvent was removed in vacuoto give 12.4 g of crude product. The crude product was purified by flashchromatography (SiO₂, Hexane:EtOAc 7:3) to give 12.1 g of3-methyl-phthalic acid dimethyl ester as oil: ¹H NMR (CDCl₃) δ 7.84-7.81(dd, J=1.3 and 7.1 Hz, 1H), 7.42-7.32 (m, 2H), 3.94 (s, 3H), 3.88 (s,31H), 2.35 (s, 3H).

5.1.2 3-Bromomethyl-phthalic Dimethyl Ester

A stirred mixture of 3-methyl-phthalic dimethyl ester (12.1 g, 57.9mmol) and N-bromosuccinimide (12.4 g, 69.5 mmol) in acetonitrile (150mL) was heated at 70° C. (oil bath), while a 200W light bulb situated 2cm away was shining on the reaction mixture overnight. The resultingmixture was cooled and concentrated. The residue was dissolved in ethylacetate (150 mL), washed with water (3×50 mL) and brine (50 mL), anddried (MgSO₄). Solvent was removed in vacuo, and the residue waspurified by flash chromatography (SiO₂, Hexane:EtOAc 8:2) to give3-bromomethyl-phthalic dimethyl ester (13.9 g, 83%) as a solid: ¹H NMR(CDCl₃) δ 7.94-7.90 (dd, J=1.1 and 7.9 Hz, 1H), 7.65-7.62 (dd, J=1.0 and6.9 Hz, 1H), 7.47 (t, J=7.8H, 1H), 4.54 (s, 2H), 3.97 (s, 3H), 3.90 (s,3H).

5.1.3 Methyl-carbamic Acid t-Butyl Ester

A stirred solution of 2 M methylamine/THF (30 mL, 60 mmol) andtriethylamine (6.1 g, 66 mmol) in methylene chloride (50 mL) was cooledto −20° C. A solution of di-t-butyl dicarbonate (14.4 g, 66 mmol) inmethylene chloride (50 mL) was added slowly at −10 to −20° C. Afteraddition, the mixture was stirred at −20° C. for 30 minutes, then warmedto room temperature overnight. The mixture was washed with water (2×40mL) and brine (40 mL), and dried (MgSO₄). Solvent was removed, and theresidue was stirred with hexane (15 mL). The mixture was filtered, andthe filtrate was concentrated. The residue was purified bychromatography (SiO₂, Hexane: EtOAc 8:2) to give methyl-carbamic acidt-butyl ester (6.6 g, 84%) as oil: ¹H NMR (CDCl₃) δ 4.57 (b. 1H), 2.74(d, J=4.9 Hz, 3H), 1.44 (s, 9H).

5.1.4 3-[(t-Butoxycarbonyl-Methyl-Amino)-Methyl]-Phthalic Acid DimethylEster

A solution of methyl-carbamic acid t-butyl ester (5.0 g, 38.0 mmol) inDMF (50 mL) was chilled in an ice bath, and NaH (60%, 1.7 g, 41.8 mmol)was added in portions at 10C. The mixture was stirred for an additional30 minutes. A solution of 3-bromomethyl-phthalic acid dimethyl ester(10.9 g, 38.0 mmol) in DMF (20 mL) was slowly added, keeping thetemperature at 10-15° C. The resulting mixture was stirred at roomtemperature overnight. The mixture was poured into ice water (400 mL)and extracted with EtOAc (4×70 mL). The combined EtOAc extracts werewashed with water (3×50 mL) and brine (50 mL), and dried (MgSO₄). Thesolvent was removed in vacuo, and the residue was purified by flashchromatography (SiO₂, Hexane:EtOAc 8:2) to give3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic dimethyl ester (7.7g, 60%) as an oil: ¹H NMR (CDCl₃) δ 7.93-7.89 (m, 1H), 7.49-7.46 (m,2H), 4.46 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 2.87-2.76 (b, 3H),1.49-1.42 (b, 9H).

5.1.5[2-(2,6-Dioxo-Piperidin-3-yl)-1,3-Dioxo-2,3-Dihydro-1H-Isoindol-4-yl-Methyl]-Methyl-CarbamicAcid t-Butyl Ester

Step 1: Sodium hydroxide (0.6 g, 15.4 mmol) was added to a stirredsolution of 3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic dimethylester (2.6 g 7.7 mmol) in ethanol (30 mL) and water (6 mL). The mixturewas heated at reflux for 1 hour. The mixture was cooled and concentratedin vacuo. Water (30 mL) was added to the residue, and the resultingmixture was washed with ether (30 mL). The aqueous layer was cooled andacidified with 6N HCl to a pH of 2. The resulting mixture was extractedwith CH₂Cl₂ (3×30 mL) and dried over MgSO₄. The solvent was removed invacuo to give a mixture of3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic acid and itsisomeric monomethyl ester, which was used in next step without furtherpurification.

Step 2: A stirred mixture of3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic acid (2.3 g, 7.1mmol) from above and α-aminoglutarimide hydrochloride (1.3 g, 7.8 mmol)in pyridine (40 mL) was refluxed for 5 hours. The mixture was cooled andconcentrated in vacuo. The residue was dissolved in EtOAc (100 mL) andwater (50 mL). The EtOAc solution was separated and washed with water(40 mL), IN citric acid (2×40 mL), water (2×40 mL), and brine (40 mL),and then dried (MgSO₄). Solvent was removed in vacuo, and the residuewas purified by flash chromatography (SiO₂, CH₂Cl₂: EtOAc 8:2) to give[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamicacid t-butyl ester (1.7 g, 60%): mp 138-140° C.; ¹H NMR (DMSO-d₆) δ11.14 (s, 1H), 7.91-7.81 (m, 2H), 7.57 (b, 1H), 5.19-5.12 (dd, J=5.3 and12.6 Hz, 1H), 4.85 (s, 2H), 2.97-2.83 (m, 1H), 2.89 (s, 3H), 2.63-2.50(m, 2H), 2.07-2.03 (m, 1H), 1.44-1.29 (d, 9H); ¹³CNMR (DMSO-d₆) δ172.70, 169.74, 167.48, 166.87, 154.75, 138.31, 134.99, 132.31, 131.74,127.42, 121.98, 79.13, 48.86, 47.32, 34.84, 30.90, 27.93, 21.94; Anal.Calcd. for C₂₀H₂₃N₃O₆: C, 59.84; H, 5.78; N, 10.47. Found: C, 59.51; H,5.68; N, 10.31. 5.22-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindol-1,3-dionehydrochloride

To a stirred solution of[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamicacid t-butyl ester (8.1 g, 20.2 mmol) in methylene chloride (80 mL), wasadded 2N HCl/ether (25 mL). The mixture was stirred at room temperatureovernight. The mixture was filtered, washed with CH₂Cl₂ (20 mL), anddried to afford2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindol-1,3-dionehydrochloride (5.3 g, 77%) as an off white solid: ¹H NMR (DMSO-d₆) δ11.17 (s, 1H), 9.64 (s, 2H), 8.11-7.91 (m, 3H), 5.22-5.15 (dd, J=4.9 and12.5 Hz, 1H), 4.55 (s, 2H), 2.98-2.84 (m, 1H), 2.64-2.50 (m, 2H), 2.60(s, 3H), 2.08-2.03 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.69, 169.60, 167.22,166.51, 136.40, 134.86, 131.45, 130.65, 129.20, 123.88, 48.89, 45.66,32.39, 30.84, 21.96.

5.3 cyclopropanecarboxylic acid12-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl1-methyl-amide

Triethylamine (0.50 g, 4.8 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindol-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and cyclopropanecarbonyl chloride (0.2g, 2.1 mmol) in THF (20 mL) at 5° C. After addition, the mixture wasstirred at room temperature for 2 hours. The mixture was concentrated invacuo, and the solid residue was stirred with 1N HCl (25 mL). The crudeproduct was slurried with hot EtOAc (15 mL) to give 0.5 g (74%) of theproduct as a white solid: mp 243-245° C.; ¹H NMR (DMSO-d₆) δ 11.13 (s,1H), 7.91-7.82 (m, 2H), 7.57-7.45 (m, 1H), 5.19-5.14 (dd, J=4.2 and 12.2Hz, 1H), 4.97 (s, 2H), 3.21 (s, 3H), 2.92-2.85 (m, 1H), 2.64-2.51 (m,2H), 2.08-1.84 (m, 2H), 0.81-0.63 (m, 4H); ¹³C NMR (DMSO-d₆) δ 173.16,172.71, 169.77, 167.55, 166.89, 138.05, 135.25, 134.93, 132.54, 131.74,127.58, 121.90, 48.87, 46.35, 35.63, 30.91, 21.96, 10.62, 7.28; Anal.Calcd. for C₁₉H₁₉N₃O₅: C, 61.78; H, 5.18; N, 11.38. Found: C, 61.58; H,4.90; N, 11.21.

5.4N-[2-(2,6-dioxo-piperidin-3-YL)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-N-methyl-propionamide

Triethylamine (0.5 g, 4.8 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindol-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and propionyl chloride (0.3 g, 2.7 mmol)in THF (30 mL). The mixture was stirred at room temperature overnight.Reaction mixture was quenched with methanol (1 mL) and concentrated.Residue was dissolved in methylene chloride (70 mL) and washed with 1NHCl (30 mL), water (30 mL), and brine (30 mL) and then dried (MgSO₄).Solvent was removed, and residue was purified by chromatography (SiO₂,CH₂Cl₂: EtOAc 8:2) to give 0.3 g (36%) of product as white solid: mp206-208° C.; ¹H NMR (DMSO-d₆) δ 11.14 (s, 1H), 7.89-7.81 (m, 2H), 7.53(m, 1H), 5.19-5.12 (dd, J=4.9 and 12.4 Hz, 1H), 4.95 (5.03) (s, 2H),3.03 (2.87) (s, 3H), 2.87 (In, 1H), 2.63-2.29 (m, 4H), 2.08-1.99 (m,1H), 1.09-0.97 (m, 3H); ¹³C NMR (DMSO-d₆) δ 173.44, 172.66, 169.72,167.50, 166.84, 138.08, 134.80, 132.52, 131.67, 127.49, 121.79, 48.79,46.13, 35.38, 30.84, 25.52, 21.88, 9.06; Anal. Calcd. for C₁₈H₁₉N₃O₅: C,60.50; H, 5.36; N, 11.76. Found: C, 60.37; H, 5.52; N, 11.41.

5.53-cyclohexyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Triethylamine (0.30 g, 2.9 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and cyclohexyl isocyanate (0.30 g, 2.5mmol) in THF (20 mL). The mixture was stirred at room temperature for 3hours. The reaction mixture was concentrated in vacuo, and residue wasdissolved in methylene chloride (80 mL), washed with 1N HCl (30 mL),water (30 mL), and brine (30 mL) and then dried (MgSO₄). The solvent wasremoved in vacuo, and the residue was slurried with EtOAc (10 mL) togive 0.7 g, (79%) of product as white solid: mp 243-245° C.; ¹H NMR(DMSO-d₆) δ 11.14 (s, 1H), 7.88-7.78 (m, 2H), 7.50-7.47 (m, 1H), 6.19(d, J=7.8 Hz, 1H), 5.19-5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.88 (s, 2H),3.45 (b, 1H), 2.96-2.85 (m, 1H), 2.83 (s, 3H), 2.63-2.51 (m, 2H),2.07-1.98 (m, 1H), 1.77-1.54 (m, 5H), 1.26-1.02 (m, 5H); ¹³C NMR(DMSO-d₆) δ 172.72, 169.78, 167.59, 166.96, 157.30, 139.46, 134.80,132.46, 131.73, 127.49, 121.69, 49.36, 48.83, 47.13, 34.55, 33.12,30.91, 25.33, 25.10, 21.97; Anal. Calcd. for C₂₂H₂₆N₄O₅+0.25H₂O: C,61.31; H, 6.20; N, 13.00. Found: C, 61.13; H, 6.12; N, 12.91.

5.61-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1,3,3-Trimethylrurea

1,8-Diazabicyclo[5,4,0]undec-7-ene (0.80 g, 5.4 mmol) was added to astirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and dimethylcarbamoyl chloride (0.30 g,2.9 mmol) in acetonitrile (60 mL). The mixture was stirred at roomtemperature overnight. The reaction mixture was then concentrated invacuo, and the residue was dissolved in methylene chloride (80 mL),washed with 1N HCl (30 mL), water (30 mL), and brine (30 mL), and thendried (MgSO₄). Solvent was removed in vacuo, and the residue purified bychromatography (SiO₂, CH₂Cl₂: CH₃OH 97.5:2.5) to give 0.6 g (80%) ofproduct as white solid: mp 206-208° C.; ¹H NMR (DMSO-d₆) δ 11.14 (s,1H), 7.89-7.69 (m, 3H), 5.19-5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.74 (s,2H), 2.92-2.83 (m, 1H), 2.78 (s, 6H), 2.75 (s, 3H), 2.63-2.50 (m, 2H),2.08-2.03 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.72, 169.79, 167.44, 166.92,164.21, 138.73, 134.77, 133.23, 131.80, 127.76, 121.86, 48.83, 38.26,37.17, 30.90, 21.95; Anal. Calcd. for C₁₈H₂₀N₄O₅: C, 58.06; H, 5.41; N,15.05. Found: C, 57.85; H, 5.36; N, 14.82.

5.71-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(3-methoxy-phenyl)-1-methyl-urea

Triethylamine (0.30 g, 2.9 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and 3-methoxyphenyl isocyanate (0.40 g,2.5 mmol) in THF (20 mL). The mixture was stirred at room temperaturefor 3 hours. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (80 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the residue was purified bychromatography (SiO₂, CH₂Cl₂: EtOAc 6:4) to give 0.7 g (83%) of productas yellow solid: mp 160-162° C.; ¹H NMR (DMSO-d₆) δ 11.13 (s, 1H), 8.47(s, 1H), 7.89-7.81 (m, 2H), 7.62-7.60 (m, 1H), 7.19-7.08 (m, 3H),6.54-6.51 (m, 1H), 5.20-5.13 (dd, J=5.3 and 12.6 Hz, 1H), 5.01 (s, 2H),3.70 (s, 3H), 3.04 (s, 3H), 2.91-2.84 (m, 1H), 2.64-2.49 (m, 2H),2.09-2.05 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.72, 169.79, 167.57, 166.95,159.31, 155.61, 141.58, 138.80, 134.97, 132.43, 131.80, 128.92, 127.57,121.87, 112.09, 107.41, 105.49, 54.86, 48.86, 47.48, 35.14, 30.92,21.98; Anal. Calcd. for C₂₃H₂₂N₄O₆+0.21H₂O: C, 60.82; H, 4.98; N, 12.33.Found: C, 60.95; H, 4.98; N, 11.93.

5.81-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-1-methyl-urea

Triethylamine (0.30 g, 2.9 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.70 g, 1.9 mmol) and 4-methoxyphenyl isocyanate (0.40 g,2.5 mmol) in THF (20 mL). The mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (70 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the solid residue was slurried withhot methanol (10 mL) to give 0.6 g (72%) of product as white solid: mp243-245° C.; ¹H NMR (DMSO-d₆) δ 11.15 (s, 1H), 8.37 (s, 1H), 7.90-7.81(m, 2H), 7.62-7.59 (m, 1H), 7.35 (d, J=8.9 Hz, 2H), 6.84 (d, J=8.9 Hz,2H), 5.20-5.13 (dd, J=5.2 and 12.5 Hz, 1H), 5.00 (s, 2H), 3.70 (s, 3H),3.03 (s, 3H), 2.91-2.84 (m, 1H), 2.64-2.49 (m, 2H), 2.09-2.04 (m, 1H);¹³C NMR (DMSO-d₆) δ 172.73, 169.80, 167.58, 166.96, 155.98, 154.60,138.99, 134.94, 133.27, 132.45, 131.78, 127.58, 121.95, 121.82, 113.42,55.08, 48.85, 47.44, 35.05, 30.92, 21.97; Anal. Calcd. for C₂₃H₂₂N₄O₆:C, 61.33; H, 4.92; N, 12.44. Found: C, 61.15; H, 4.81; N, 12.26.

5.91-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methyl-phenyl)-1-methyl-urea

Triethylamine (0.3 g, 2.7 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and p-tolyl isocyanate (0.30 g, 2.5mmol) in THF (40 mL). The mixture was stirred at room temperatureovernight. Reaction mixture was concentrated, and solid residue wasstirred with 1N HCl (30 mL). Solid was collected and reslurried with hotreagent alcohol (15 mL) to give 0.8 g (89%) of product as white solid:mp>260° C.; ¹H NMR (DMSO-d₆) δ 11.14 (s, 1H), 8.41 (s, 1H), 7.89-7.80(m, 2H), 7.62-7.60 (m, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.2 Hz,2H), 5.20-5.13 (dd, J=5.3 and 12.5 Hz, 1H), 5.00 (s, 2H), 3.03 (s, 3H),2.91-2.84 (m, 1H), 2.64-2.50 (m, 2H), 2.22 (s, 3H), 2.08-2.05 (m, 1H);¹³CNMR (DMSO-d₆) δ 172.75, 169.82, 167.59, 166.97, 155.81, 138.93,137.73, 134.96, 132.45, 131.80, 130.73, 129.11, 128.63, 127.57, 121.85,120.16, 118.17, 48.86, 47.46, 35.11, 30.93, 21.98, 20.32; Anal. Calcd.for C₂₃H₂₂N₄O₅: C, 63.59; H, 5.10; N, 12.90. Found: C, 63.68; H, 4.96;N, 12.66.

5.101-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-ethyl-1-methyl-urea

Triethylamine (0.3 g, 2.7 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and ethyl isocyanate (0.2 mL, 2.5 mmol)in THF (40 mL) at room temperature. The mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo,and the residue was stirred with 1N HCl (30 mL). The resulting solid wascollected and reslurried with acetone (10 mL) to give 0.5 g (68%) ofproduct as white solid: mp 219-221° C.; ¹H NMR (DMSO-d₆) δ 11.14 (s,1H), 7.88-7.78 (m, 2H), 7.51-7.48 (m, 1H), 6.51 (t, J=5.4 Hz, 1H),5.19-5.12 (dd, J=5.4 and 12.5 Hz, 1H), 4.88 (s, 2H), 3.13-3.02 (m, 2H),2.92-2.89 (m, 1H), 2.86 (s, 3H), 2.63-2.49 (m, 2H), 2.08-2.03 (m, 1H),1.02 (t, J=7.0 Hz, 3H); ¹³CNMR (DMSO-d₆) δ 172.73, 169.80, 167.58,166.99, 157.90, 139.48, 134.84, 132.40, 131.74, 127.48, 121.70, 48.83,47.16, 35.00, 34.51, 30.92, 21.98, 15.64; Anal. Calcd. for C₁₈H₂₀N₄O₅;C, 58.06; H, 5.41; N, 15.05. Found: C, 57.93; H, 5.10; N, 14.86.

5.111-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(3-methyl-phenyl)-1-methyl-urea

Triethylamine (0.30 g, 2.7 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.70 g, 1.9 mmol) and m-tolyl isocyanate (0.30 g, 2.5mmol) in THF (40 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (80 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and solid residue was slurried with ether(20 mL) to give 0.7 g (77%) of product as white solid: mp 212-215° C.;¹H NMR (DMSO-d₆) δ 11.15 (s, 1H), 8.43 (s, 1H), 7.90-7.81 (m, 2H),7.62-7.59 (dd, J=1.1 and 7.1 Hz, 1H), 7.33-7.28 (m, 2H), 7.11 (t, J=7.6Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 5.21-5.13 (dd, J=5.4 and 12.6 Hz, 1H),5.01 (s, 2H), 3.04 (s, 3H), 2.98-2.84 (m, 1H), 2.64-2.49 (m, 2H), 2.24(s, 3H), 2.09-2.05 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.74, 169.81, 167.59,166.97, 155.72, 140.23, 138.89, 137.26, 134.98, 132.43, 131.80, 128.07,127.57, 122.63, 121.86, 120.52, 117.11, 48.87, 47.48, 35.14, 30.93,21.99, 21.15; Anal. Calcd. for C₂₃H₂₂N₄O₅: C, 63.59; H, 5.10; N, 12.90.Found: C, 63.48; H, 4.94; N, 12.74.

5.123-benzo[1,3]dioxo-5-yl-1-[2-(2,6-dioxo-piperidin-3-yl)-,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Triethylamine (0.30 g, 2.7 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.70 g, 1.9 mmol) and 3,4-methylenedioxyphenyl isocyanate(0.40 g, 2.5 mmol) in THF (40 mL). The mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo,and the residue was stirred with 1N HCl (30 mL). Solid was collected andreslurried with acetone (15 mL) to give 0.8 g (90%) of product as whitesolid: mp 258-260° C.; ¹H NMR (DMSO-d₆) δ 11.15 (s, 1H), 8.40 (s, 1H),7.90-7.81 (m, 2H), 7.62-7.58 (m, 1H), 7.17-7.15 (m, 1H), 6.89-6.74 (m,2H), 5.94 (s, 2H), 5.20-5.13 (dd, J=5.4 and 12.6 Hz, 1H), 4.99 (s, 2H),3.02 (s, 3H), 2.93-2.83 (m, 1H), 2.64-2.50 (m, 2H), 2.08-2.04 (m, 1H);¹³CNMR (DMSO-d₆) δ 172.75, 169.81, 167.58, 166.97, 155.87, 146.77,142.15, 138.87, 134.98, 134.64, 132.46, 131.80, 127.57, 121.86, 112.92,107.56, 102.73, 100.68, 48.86, 47.46, 35.07, 30.93, 21.98; Anal. Calcd.for C₂₃H₂₀N₄O₇: C, 59.48; H, 4.34; N, 12.06. Found: C, 59.33; H, 4.08;N, 11.72.

5.131-[2-(2,6-dioxo-piperidin-3-yl)-1,3-DIOXO-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-naphthalen-2-yl-urea

Triethylamine (0.30 g, 2.7 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoidnole-1,3-dionehydrochloride (0.70 g, 1.9 mmol) and 2-naphthyl isocyanate (0.40 g, 2.1mmol) in THF (40 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated, and residue wasstirred with 1N HCl (30 mL). The solid was collected by filtration andreslurried in ether (15 mL) to give 0.8 g (92%) of product as whitesolid: mp>260° C.; ¹H NMR (DMSO-d₆) δ 11.16 (s, 1H), 8.74 (s, 1H), 8.07(s, 1H), 7.91-7.65 (m, 7H), 7.45-7.32 (m, 2H), 5.22-5.15 (dd, J=5.0 and12.6 Hz, 1H), 5.07 (s, 2H), 3.11 (s, 3H), 2.92-2.87 (m, 1H), 2.65-2.50(m, 2H), 2.08 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.75, 169.82, 167.60,166.97, 155.82, 138.82, 138.07, 135.02, 133.45, 132.48, 131.83, 129.16,127.66, 127.60, 127.32, 126.92, 126.08, 123.96, 121.90, 121.25, 115.29,48.88, 47.57, 35.21, 30.94, 22.00; Anal. Calcd. for C₂₆H₂₂N₄O₅: C,66.38; C, 4.71; N, 11.91. Found: C, 66.25; H, 4.36; N, 11.67.

5.141-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-phenyl-urea

Triethylamine (0.30 g, 2.7 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.70 g, 1.9 mmol) and phenyl isocyanate (0.30 g, 2.3mmol) in THF (40 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (80 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the solid residue was slurried withreagent alcohol (20 mL) to give 0.6 g (79%) of product as white solid:mp 226-228° C.; ¹H NMR (DMSO-d₆) δ 11.14 (s, 1H), 8.51 (s, 1H),7.90-7.81 (m, 2H), 7.63-7.60 (m, 1H), 7.47 (d, J=7.6 Hz, 2H), 7.23 (t,J=7.7 Ha, 2H), 6.94 (t, J=7.3 Hz, 1H), 5.20-5.13 (dd, J=5.4 and 12.5 Hz,1H), 5.01 (s, 2H), 3.05 (s, 3H), 2.96-2.83 (m, 1H), 2.64-2.53 (m, 2H),2.09-2.05 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.75; 169.81, 167.59, 166.97,155.75, 140.33, 138.84, 134.98, 132.45, 131.81, 128.22, 127.59, 121.92,121.88, 119.98, 48.86, 47.48, 35.15, 30.93, 21.98; Anal. Calcd. forC₂₂H₂₀N₄O₅: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.55; H, 4.53; N,13.10.

5.151-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-Ylmethyl]-1-methyl-3-propyl-urea

Triethylamine (0.30 g, 2.9 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.70 g, 1.9 mmol) and propyl isocyanate (0.20 g, 2.3mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (70 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the residue was purified bychromatography (SiO₂, CH₂Cl₂: CH₃OH 95:5) to give 0.5 g (78%) of productas white solid: mp 210-212° C.; ¹H NMR (DMSO-d₆) δ 11.15 (s, 1H),7.88-7.78 (m, 2H), 7.50-7.47 (m, 1H), 6.53 (t, J=5.5 Hz, 1H), 5.19-5.12(dd, J=5.4 and 12.5 Hz, 1H), 4.88 (s, 2H), 3.02 (q, J=6.4 Hz, 2H),2.92-2.83 (m, 1H), 2.87 (s, 3H), 2.63-2.47 (m, 2H), 2.08-2.03 (m, 1H),1.46-1.35 (m, 2H), 0.82 (t, J=7.3 Hz, 3H); ¹³CNMR (DMSO-d₆) δ 172.76,169.83, 167.59, 167.00, 157.98, 139.50, 134.85, 132.35, 131.76, 127.50,121.71, 48.83, 47.23, 42.04, 34.57, 30.93, 23.70, 21.99, 11.32; Anal.Calcd. for C₁₉H₂₂N₄O₅: C, 59.06; H, 5.74; N, 14.50. Found: C, 58.98; H,5.83; N, 14.22.

5.16[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamicacid tert-butyl ester

5.16.1 3-[(tert-Butoxycarbonyl-Methyl-Amino)-Methyl]-Phthalic Acid2-Methyl Ester

A solution of sodium hydroxide (0.5 g, 13.3 mmol) in H₂O (5 mL) wasadded to a stirred solution of3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phthalic acid dimethylester (3.9 g, 11.1 mmol) in ethylene glycol dimethyl ether (10 mL). Themixture was stirred at room temperature overnight. The mixture wasextracted with ether (25 mL) to give 0.2 g of recovered startingmaterial. The aqueous layer was cooled and acidified with 4N HCl. Themixture was extracted with methylene chloride (3×35 mL) and concentratedin vacuo to afford 3.5 g of the desired product as an oil: ¹H NMR(CDCl₃) δ 8.02-7.99 (m, 1H), 7.52-7.50 (m, 2H), 4.48 (s, 2H), 3.92 (s,3H), 2.84-2.78 (m, 3H), 1.49-1.43 (m, 9H).

5.16.26-[(tert-Butoxycarbonyl-Methyl-Amino)-Methyl]-N,N-Diethyl-PhthalamicAcid Methyl Ester

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.60 g,18.5 mmol) was added to a stirred solution of diethylamine (1.40 g, 18.5mmol), 1-hydroxybenzotriazol (2.50 g, 18.5 mmol) and3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phthalic acid 2-methylester (4.60 g, 14.2 mmol) in DMF (40 mL). The mixture was stirred atroom temperature overnight. The reaction mixture was then poured intowater (100 mL) and extracted with EtOAc (3×40 mL). The combined EtOACextracts were washed with water (2×40 mL) and brine (40 mL), and dried(MgSO₄). Solvent was removed in vacuo, and the residue was purified byflash chromatography (SiO₂, CH₂Cl₂: EtOAc 8:2) to give 4.3 g (79%) ofproduct as an oil: ¹H NMR (CDCl₃) δ 7.44 (t, J=7.6 Hz, 1H), 7.29 (d,J=6.8 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 4.62 (s, 2H), 3.83 (s, 3H),3.57-3.48 (q, J=7.0 Hz, 2H), 3.24-3.16 (q, J=7.0 Hz, 2H), 2.85 (s, 3H),1.48-1.42 (m, 9H), 1.23 (t, J=7.0 Hz, 3H), 1.09 (t, J=7.0 Hz, 3H).

5.16.3 (3-Diethylcarbamoyl-2-Hydroxymethyl-Benzyl)-Methyl-Carbamic Acidtert-Butyl Ester

A stirred mixture of lithium borohydride (0.800 g, 35.4 mmol) in dryether (80 mL) was cooled to 5° C. in an ice bath. A solution of6-[(tert-butoxycarbonyl-methyl-amino)-methyl]-N,N-diethyl-phthalamicacid methyl ester (8.90 g, 23.6 mmol) in THF (30 mL) was added slowly at5-10° C. After the addition was complete, the mixture was stirred atroom temperature overnight. The reaction mixture was then cooled in anice bath and quenched by the addition of water (35 mL). The aqueouslayer was extracted with EtOAc (2×40 mL). The combined organic solutionswere washed water (2×40 mL) and brine (40 mL), and dried (MgSO₄).Solvent was removed in vacuo to give 7.9 g (96%) of product as an oil,which was used in next step without further purification.

5.16.4 Methanesulfonic Acid2-[(tert-Butoxycarbonyl-Methyl-Amino)-Methyl]-6-Diethylcarbamoyl-BenzylEster

A stirred solution of(3-diethylcarbamoyl-2-hydroxymethyl-benzyl)-methyl-carbamic acidtert-butyl ester (7.9 g, 22.7 mmol) and triethylamine (3.7 g, 36.3 mmol)in dry methylene chloride (110 mL) was cooled to 0° C. Methanesulfonylchloride (3.1 g, 27.3 mmol) was added at 0-3° C. The mixture was stirredat 0° C. for 30 minutes then washed with water (40 mL) and brine (40mL), and dried (MgSO₄). The solvent was removed in vacuo and the crudeproduct (9.7 g) was used in next reaction.

5.16.5[2-(2,6-Dioxo-Piperidin-3-yl)-1-Oxo-2,3-Dihydro-1H-Isoindol-4-yl-Methyl]-Methyl-CarbamicAcid tert-Butyl Ester

Triethylamine (4.60 g, 45.4 mmol) was added to a stirred suspension ofmethanesulfonic acid2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-6-diethylcarbamoyl-benzylester (9.70 g, 22.7 mmol) and α-aminoglutarimide hydrochloride (3.40 g,20.4 mmol) at room temperature in acetonitrile (80 mL). The mixture wasstirred at room temperature overnight. Glacial acetic acid (13.6 g, 227mmol) was added, and the mixture was heated at 82° C. oil bath for 4hours. The mixture was cooled and concentrated in vacuo. The residue wasdissolved in EtOAc (200 mL) and washed with water (50 mL), sat. NaHCO₃(50 mL), water (2×50 mL), and brine (50 mL), and then dried (MgSO₄). Thedark dried solution was treated with decolorizing carbon and filteredagain. The solvent was removed in vacuo, and the residue was slurriedwith ether (30 mL) to give 4.5 g (57%) of product as white solid: ¹H NMR(DMSO-d₆) δ 11.03 (s, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.53 (t, J=7.3 Hz,1H), 7.43 (d, J=7.4 Hz, 1H), 5.19-5.12 (dd, J=4.6 and 13.0 Hz, 1H),4.55-4.25 (m, 4H), 3.00-2.86 (m, 1H), 2.78 (s, 3H), 2.62-2.58 (m, 1H),2.35-2.30 (m, 1H), 2.05-2.01 (m, 1H), 1.40 (s, 9H); ¹³CNMR (DMSO-d₆) δ172.81, 170.98, 167.96, 154.91, 140.03, 133.48, 131.92, 130.11, 128.43,121.89, 79.07, 51.52, 48.20, 46.13, 34.09, 31.14, 27.97, 22.66.

5.173-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride

A solution of 2N HCl in ether (20 mL, 40 mmol) was added to a stirredsolution of[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamicacid tert-butyl ester (4.5 g, 11.6 mmol) in methylene chloride (90 mL).The mixture was stirred at room temperature for 2 days. The reactionsuspension was filtered, washed with methylene chloride, and dried togive 3.7 g (98%) of product as white solid: ¹H NMR (DMSO-d₆) δ 11.06 (s,1H), 9.47-9.37 (b, 2H), 7.85 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H),7.61 (t, J=7.6 Hz, 1H), 5.22-5.15 (dd, J=4.9 and 13.0 Hz, 1H), 4.74 (d,J=17.5 Hz, 1H), 4.53 (d, J=17.5 Hz, 1H), 4.17 (s, 2H), 3.02-2.88 (m,1H), 2.67-2.59 (m, 1H), 2.59 (s, 3H), 2.42-2.28 (m, 1H), 2.04-2.00 (m,1H); ¹³C NMR (DMSO-d₆) δ 172.86, 170.93, 167.68, 142.22, 133.47, 132.05,128.54, 127.57, 123.74, 51.50, 47.36, 46.29, 32.44, 31.13, 22.77.

5.183-(3,4-dimethylphenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Triethylamine (0.30 g, 2.6 mmol) was added to stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.6 g, 1.9 mmol) and 3,4-dimethylphenyl isocyanate (0.30g, 2.2 mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (80 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄).Solvent was removed in vacuo, and the residue was purified bychromatography (SiO₂, CH₂Cl₂: CH₃OH 95:5) to give 0.6 g (76%) of productas white solid: mp 228-230° C.; ¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 8.29(s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.45 (d, J=7.4Hz, 1H), 7.23-7.15 (m, 2H), 6.99 (d, J=8.2 Hz, 1H), 5.17-5.10 (dd, J=5.0and 13.2 Hz, 1H), 4.63 (s, 2H), 4.42 (d, J=17.4 Hz, 1H), 4.36 (d, J=17.2Hz, 1H), 2.95 (s, 3H), 2.92-2.87 (m, 1H), 2.62-2.55 (m, 1H), 2.34-2.27(m, 1H), 2.15 (s, 3H), 2.13 (s, 3H), 2.13-2.01 (m, 1H); ¹³CNMR (DMSO-d₆)δ 172.77, 170.94, 167.99, 155.68, 140.10, 137.96, 135.67, 133.91,131.90, 129.91, 129.51, 129.15, 128.38, 121.67, 121.48, 117.65, 51.55,48.38, 46.25, 34,63, 31.14, 22.54; Anal. Calcd. for C₂₄H₂₆N₄O₄: C,66.34; H, 6.03; N, 12.89. Found: C, 66.11; H, 6.17; N, 12.66.

5.193-(3-chloro-4-methyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Triethylamine (0.3 g, 2.6 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and 3-chloro-4-methylphenyl isocyanate(0.40 g, 2.2 mmol) in THF (30 mL). The mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo,and the residue was stirred with 1N HCl (30 mL). The resultingsuspension was collected, and the collected solid slurried with acetone(15 mL) to give 0.6 g (75%) of product as white solid: mp 248-250° C.;¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 8.55 (s, 1H), 7.67-7.64 (m, 2H), 7.53(t, J=7.8 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.36-7.31 (dd, J=2.0 and 8.3Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 5.18-5.10 (dd, J=4.8 and 13.2 Hz, 1H),4.64 (s, 2H), 4.44 (d, J=17.5 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 2.97 (s,3H), 2.97-2.85 (m, 1H), 2.63-2.56 (m, 1H), 2.37-2.30 (m, 1H), 2.24 (s,3H), 2.08-1.99 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.79, 170.97, 167.99,155.40, 140.13, 139.63, 133.68, 132.61, 131.92, 130.69, 129.88, 128.44,128.21, 121.74, 119.71, 118.41, 51.59, 48.36, 46.27, 34.69, 31.17,22.56, 18.75; Anal. Calcd. for C₂₃H₂₃ClN₄O₄: C, 60.73; H, 5.10; Cl,7.79; N, 12.32. Found: C, 60.75; H, 5.14; Cl, 7.79; N, 12.22.

5.203-(3,4-dichloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Triethylamine (0.30 g, 2.6 mmol) was added to stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and 3,4-dichlorophenyl isocyanate (0.40g, 2.2 mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. the reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (70 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the residue was slurried with acetone(20 mL) to give 0.6 g (70%) of product as white solid: mp 275-277° C.;¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 8.75 (s, 1H), 7.86 (s, 1H), 7.64 (d,J=7.3 Hz, 1H), 7.56-7.42 (m, 4H), 5.18-5.10 (dd, J=5.0 and 13.1 Hz, 1H),4.65 (s, 2H), 4.52 (d, J=17.4 Hz, 1H), 4.38 (d, J=17.3 Hz, 1H), 2.99 (s,3H), 2.92-2.87 (m, 1H), 2.64-2.57 (m, 1H), 2.39-2.33 (m, 1H), 2.08-1.99(m, 1H); ¹³CNMR (DMSO-d₆) δ 172.78, 170.96, 167.96, 155.18, 140.73,140.13, 133.48, 131.92, 130.50, 130.10, 129.83, 128.45, 123.10, 121.77,120.70, 119.57, 51.60, 48.34, 46.25, 34.73, 31.15, 22.54; Anal. Calcd.for C₂₂H₂₀Cl₂N₄O₄: C, 55.59; H, 4.24; Cl, 14.92; N, 11.79. Found: C,55.23, H, 4.34, Cl, 15.01;N, 11.48.

5.211-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(3-methoxy-phenyl)-1-methyl-urea

Triethylamine (0.30 g, 2.6 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and 3-methoxyphenyl isocyanate (0.30 g,2.2 mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and theresidue was stirred with 1N HCl (30 mL). The solid was collected andslurried with reagent alcohol (20 mL) to give 0.6 g (73%) of product aswhite solid: mp 296-298° C.; ¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 8.44 (s,1H), 7.64 (d, J=7.3 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.46 (d, J=7.3 Hz,1H), 7.16-7.05 (m, 3H), 6.54 (d, J=7.6 Hz, 1H), 5.17-5.10 (dd, J=4.9 and13.1 Hz, 1H), 4.65 (s, 2H), 4.44 (d, J=17.4 Hz, 1H), 4.37 (d, J=17.3 Hz,1H), 3.70 (s, 3H), 2.97 (s, 3H), 2.97-2.85 (m, 1H), 2.62-2.52 (In 1H),2.35-2.30 (m, 1H), 2.04-1.99 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.82,170.99, 168.02, 159.35, 155.52, 141.64, 140.15, 133.81, 131.93, 129.92,128.98, 128.44, 121.74, 112.12, 107.35, 105.54, 54.88, 51.60, 48.39,46.29, 34.73, 31.17, 22.56; Anal. Calcd. for C₂₃H₂₄N₄O₅+0.6H₂O: C,61.76; H, 5.68; N, 12.53. Found: C, 61.51; H, 5.54; N, 12.39.

5.221-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-P-tolyl-urea

Triethylamine (0.30 g, 2.6 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and p-tolyl isocyanate (0.30 g, 2.2mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (70 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the residue was purified by flashchromatography (SiO₂, CH₂Cl₂: CH₃OH 97:3) to give 0.5 g (65%) of productas white solid: mp 238-240° C.; ¹H NMR (DMSO-d₆) δ 11.02 (s, 1H), 8.37(s, 1H), 7.63 (d, J=7.3 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.45 (d, J=7.2Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H), 5.17-5.10 (dd,J=5.1 and 13.2 Hz, 1H), 4.64 (s, 2H), 4.43 (d, J=17.4 Hz, 1H), 4.37 (d,J=17.3 Hz, 1H), 2.96-2.84 (m, 1H), 2.92 (s, 3H), 2.62-2.55 (m, 1H),2.34-2.28 (m, 1H), 2.22 (s, 3H), 2.03-1.98 (m, 1H); ¹³C NMR (DMSO-d₆) δ172.81, 170.97, 168.00, 155.71, 140.14, 137.76, 133.90, 131.91, 130.74,129.92, 128.67, 128.40, 121.69, 120.20, 51.57, 48.38, 46.27, 34.66,31.15, 22.54, 20.31; Anal. Calcd. for C₂₃H₂₄N₄O₄+0.2H₂O: C, 65.14; H,5.80; N, 13.21. Found: C, 65.27; H, 5.68; N, 13.27.

5.231-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1,33-trimethyl-urea

A stirred mixture of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol), dimethylcarbamyl chloride (0.40 g, 3.7mmol) and diisopropylethylamine (0.80 g, 6.1 mmol) in DMF (15 mL) washeated at 40° C. oil bath for 3 hours. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in methylenechloride (70 mL), washed with 1N HCl (30 mL), water (30 mL), and brine(30 mL), and then dried (MgSO₄). The solvent was removed in vacuo, andthe residue was purified by flash chromatography (SiO₂, CH₂Cl₂: CH₃OH97:3) to give 0.4 g (65%) of product as white solid: mp 212-214° C.; ¹HNMR (DMSO-d₆) δ 11.00 (s, 1H), 7.63-7.50 (m, 3H), 5.17-5.10 (dd, J=5.0and 12.5 Hz, 1H), 4.42 (d, J=17.5 Hz, 1H), 4.37 (s, 2H), 4.34 (d, J=17.5Hz, 1H), 2.97-2.85 (m, 1H), 2.75 (s, 6H), 2.71 (s, 3H), 2.64-2.58 (m,1H), 2.42-2.37 (m, 1H), 2.04-1.99 (m, 1H); ¹³C NMR (DMSO-d₆) δ 172.85,170.99, 168.03, 164.25, 140.39, 133.73, 131.79, 130.33, 128.31, 121.66,51.55, 50.24, 46.09, 38.22, 36.93, 31.18, 22.52; Anal. Calcd. forC₁₈H₂₂N₄O₄: C, 60.32; H, 6.19; N, 15.63. Found: C, 60.27; H, 6.23; N,15.49.

5.243-(4-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Triethylamine (0.30 g, 2.6 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and 4-chlorophenyl isocyanate (0.30 g,2.2 mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and the solidresidue was stirred with 1N HCl (30 mL). The solid was collected andslurried with acetone (20 mL) to give 0.5 g (65%) of product as whitesolid: mp 255-257° C.; ¹H NMR (DMSO-d₆) δ 11.02 (s, 1H), 8.59 (s, 1H),7.64 (d, J=7.3 Hz, 1H), 7.56-7.43 (m, 4H), 7.30 (d, J=8.7 Hz, 2H),5.18-5.10 (dd, J=4.8 and 13.1 Hz, 1H), 4.71 (s. 2H), 4.45 (d, J=17.3 Hz,1H), 4.38 (d, J=17.3 Hz, 1H), 2.98 (s, 3H), 2.94-2.85 (m, 1H), 2.63-2.57(m, 1H), 2.42-2.27 (m, 1H), 2.04-1.99 (m, 1H); ¹³C NMR (DMSO-d₆) δ172.85, 171.01, 168.10, 155.47, 140.16, 139.43, 133.70, 131.92, 129.87,128.45, 128.13, 125.5 1, 121.75, 121.41, 51.60, 48.35, 46.27, 34.75,31.17, 22.57; Anal. Calcd. for C₂₂H₂₁ClN₄O₄: C, 59.93; H, 4.80; Cl,8.04; N, 12.71. Found: C, 59.64; H, 4.67; Cl 7.81; N, 12.47.

5.253-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Triethylamine (0.30 g, 2.4 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and tert-butyl isocyanate (0.20 g, 2.2mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and theresidue was dissolved in methylene chloride (80 mL), washed with 1N HCl(30 mL), water (301n L), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the residue was purified by flashchromatography (SiO₂, CH₂Cl₂: CH₃OH 97:3) to give 0.5 g (74%) of productas white solid: mp 216-218° C.; ¹H NMR (DMSO-d₆) δ 11.02 (s, 1H), 7.62(d, J=7.4 Hz, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 5.60(s, 1H), 5.18-5.11 (dd, J=5.0 and 13.2 Hz, 1H), 4.52 (s, 2H), 4.37 (d,J=17.5 Hz, 1H), 4.29 (d, J=17.4 Hz, 1H), 2.99-2.86 (m, 1H), 2.76 (s,3H), 2.65-2.58 (m, 1H), 2.34-2.27 (m, 1H), 2.05-2.01 (m, 1H), 1.27 (s,9H); ¹³C NMR (DMSO-d₆) δ 172.83, 170.98, 168.03, 157.13, 140.04, 134.53,131.90, 130.26, 128.27, 121.61, 51.47, 50.07, 48.09, 45.18, 34.19,31.14, 29.15, 22.70; Anal. Calcd. for C₂₀H₂₆N₄O₄: C, 62.16; H, 6.78; N,14.50. Found: C, 62.22; H, 6.77; N, 14.46.

5.261-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-ethyl-1-methyl-urea

Triethylamine (0.30 g, 2.4 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and ethyl isocyanate (0.20 g, 2.2 mmol)in THF (30 mL). The mixture was stirred at room temperature overnight.The reaction mixture was concentrated in vacuo, and the residue wasdissolved in methylene chloride (80 mL), washed with 1N HCl (30 mL),water (30 mL), and brine (30 mL), and then dried (MgSO₄). The solventwas removed in vacuo, and residue was purified by chromatography (SiO₂,CH₂Cl₂: CH₃OH 97:3) to give 0.3 g (37%) of product as white solid: mp183-185° C.; ¹H NMR (DMSO-d₆) δ 11.02 (s, 1H), 7.61 (d, J=7.4 Hz, 1H),7.50 (t, J=7.4 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 6.45 (t, J=5.4 Hz, 1H),5.18-5.10 (dd, J=5.1 and 13.2 Hz, 1H), 4.52 (s, 2H), 4.39 (d, J=17.3 Hz,1H), 4.31 (d. J=17.4 Hz, 1H), 3.07 (q, J=6.8 Hz, 2H), 2.93-2.88 (m, 1H),2.85 (s, 3H), 2.64-2.57 (m, 1H), 2.39-2.32 (m, 1H), 2.04-1.99 (m, 1H),1.01 (t, J=7.0 Hz, 3H); ¹³C NMR (DMSO-d₆) δ 172.87, 171.02, 168.06,157.78, 140.05, 134.37, 131.86, 129.87, 128.32, 121.56, 51.55, 48.10,46.20, 35.01, 34.07, 31.18, 22.63, 15.77; Anal. Calcd. forC₁₈H₂₂N₄O₄+0.2H₂O: C, 59.72; H, 6.24; N, 15.48. Found: C, 59.54; H,6.11; N, 15.33.

5.271-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-phenyl-urea

Triethylamine (0.30 g, 2.4 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.9 mmol) and phenyl isocyanate (0.30 g, 2.2mmol) in THF (30 mL). The mixture was stirred at room temperatureovernight. Th reaction mixture was then concentrated in vacuo, and theresidue was dissolved in methylene chloride (80 mL), washed with 1N HCl(30 mL), water (30 mL), and brine (30 mL), and then dried (MgSO₄). Thesolvent was removed in vacuo, and the residue was purified bychromatography (SiO₂, CH₂Cl₂: CH₃OH 97:3) to give 0.4 g (45%) of productas white solid: mp 186-188° C.; ¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 8.45(s, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.56-7.45 (m, 4H), 7.23 (t, J=7.7 Hz,2H), 6.94 (t, J=7.3 Hz, 1H), 5.17-5.10 (dd, J=4.9 and 13.1 Hz, 1H), 4.65(s, 2H), 4.44 (d, J=17.4 Hz, 1H), 4.38 (d, J=17.3 Hz, 1H), 2.98 (s, 3H),2.92-2.84 (m, 1H), 2.62-2.56 (m, 1H), 2.41-2.26 (m, 1H), 2.08-1.99 (m,1H); ¹³C NMR (DMSO-d₆) δ 172.84, 171.00, 168.02, 155.65, 140.37, 140.15,133.85, 131.92, 129.90, 128.44, 128.27, 121.92, 121.72, 120.02, 51.59,48.38, 46.29, 34.73, 31.17, 22.56; Anal. Calcd. for C₂₂H₂₂N₄O₄+0.6H₂O:C, 63.33; H, 5.60; N, 13.43. Found: C, 63.09; H, 5.18; N, 13.16.

5.28N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-N-methyl-propionamide

Triethylamine (0.5 g, 4.8 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindol-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and propionyl chloride (0.3 g, 2.7 mmol)in THF (30 mL). Reaction mixture was stirred at room temperatureovernight. Reaction mixture was quenched with methanol (1 mL) andconcentrated. Residue was dissolved in methylene chloride (70 mL),washed with 1N HCN (30 mL), H₂O (30 mL), and brine (30 mL), and dried(MgSO₄). Solvent was removed and residue was purified by chromatography(SiO₂, EtOAc: CH₂Cl₂ 40:60) to give 0.3 g (36%) of product: mp 206-208°C.; ¹HNMR (DMSO-d₆) δ 11.14 (s, 1H), 7.89-7.81 (m, 2H), 7.53 (m, 1H),5.19-5.12 (dd, J=4.9 and 12.4 Hz, 1H), 4.95 (s, 2H), 3.03 (s, 3H), 2.87(m, 1H), 2.63-2.29 (m, 4H), 2.08-1.99 (m, 1H), 1.09-0.97 (m, 3H); ¹³CNMR(DMSO-d₆) δ 173.44, 172.66, 169.72, 167.50, 166.84, 138.08, 134.80,132.52, 131.67, 127.49, 121.79, 48.79, 46.13, 35.38, 30.84, 25.52,21.88, 9.06; Anal. Calcd. for C₁₈H₁₉N₃O₅: C, 60.50; H, 5.36; N, 11.76.Found: C, 60.37; H, 5.52; N, 11.41.

5.291-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-M-tolyl-urea

To a suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and m-tolyl isocyanate (0.29 mL, 2.23mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine (0.45 mL g,2.60 mmol). The mixture was stirred at room temperature overnight and asuspension was obtained. The reaction mixture was filtered, and thesolid was rinsed with CH₂Cl₂ and slurred with acetone to give1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-m-tolyl-ureaas a solid (0.41 g, 52%): mp 208-210° C.; HPLC: Waters Symmetry C-18,3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=2.57(99%); ¹H NMR (DMSO-d₆): δ 1.99-2.08 (m, 1H), 2.24 (s, 3H), 2.28-2.35(m, 1H), 2.55-2.62 (m, 1H), 2.85-2.92 (m, 1H), 2.96 (s, 2H), 4.36 (d,J=17.3 Hz, 1H), 4.43 (d, J=17.3 Hz, 1H), 4.64 (s, 2H), 5.10-5.17 (dd,J=5.1, 13.2 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H),7.29-7.25 (m, 2H), 7.45 (d, J=7.2 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.63(d, J=7.3 Hz, 1H), 8.38 (s, 1H). 11.02 (s, 1H). ¹³C NMR (DMSO-d₆) δ:21.17, 22.56, 31.17, 34.71, 46.25, 48.38, 51.56, 117.15, 120.57, 121.71,122.63, 128.12, 128.43, 129.87, 131.92, 133.87, 137.31, 140.13, 140.27,155.62, 168.01, 171.01, 172.84. Anal Calcd for C₂₃H₂₄N₄O₄+0.1 H₂O: C,65.42; H, 5.78; N, 13.27. Found: C, 65.25; H, 5.50; N, 13.14.

5.301-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-propyl-urea

To a suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione(0.60 g, 1.86 mmol) and propyl isocyanate (0.21 mL, 2.23 mmol) in dryCH₂Cl₂ (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol).The mixture was stirred at room temperature overnight. The mixture wasquenched with MeOH and extracted with H₂O (40 mL), then with 1N HCl (40mL). The organic layer was washed with brine (40 mL) and concentrated onrota-vap. The resulting oil was purified on silica gel column to give1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-propyl-urea(0.33 g, 48%): mp 220-222° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, 30/70 (CH₃CN/H₂O): t_(R)=2.01 (99%); ¹H NMR(DMSO-d₆): δ 0.81 (t, J=7.3 Hz, 3H), 1.34-1.48 (m, 2H), 2.00-2.04 (m,1H), 2.30-2.37 (m, 1H), 2.58-2.64 (m, 3H), 2.78 (s, 3H), 2.86-3.04 (m,3H), 4.30 (d, J=17.3 Hz, 1H), 4.38 (d, J=17.5 Hz, 1H), 4.52 (s, 2H),5.11-5.18 (dd, J=4.9, 13.1 Hz, 1H), 6.45 (t, J=5.3 Hz, 1H), 7.37 (d,J=7.4 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 11.02 (s,1H). ¹³C NMR (DMSO-d₆) δ: 11.31, 22.63, 23.19, 31.16, 34.05, 42.01,46.14, 48.15, 51.49, 121.55, 128.30, 129.88, 131.86, 134.37, 140.02,157.81, 168.03, 171.00, 172.85. Anal Calcd for C₁₉H₂₄N₄O₄: C, 61.28; H,6.50; N, 15.04. Found: C, 60.94; H, 6.62; N, 14.89.

5.313-cyclohexyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

To a suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and cyclohexyl isocyanate (0.28 mL,2.23 mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine (0.45mL g, 2.60 mmol). The mixture was stirred at room temperature overnight.The mixture was quenched with MeOH and extracted with H₂O (40 mL), thenwith 1N HCl (40 mL). The organic layer was washed with brine (40 mL) andconcentrated on rota-vap. The resulting oil was purified on silica gelcolumn to give 3-cyclohexyl-1-[2-(2,6-dioxo-piperidin-3-yl)1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.54 g, 71%):mp 219-221° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1mL/min, 240 nm, 30/70 (CH₃CN/H₂O): t_(R)=4.61 (99%); ¹H NMR (DMSO-d₆): δ1.02-1.30 (m, 5H), 1.54-1.76 (m, 5H), 2.00-2.05 (m, 1H), 2.29-2.36 (m,1H), 2.58-2.64 (m, 1H), 2.76 (s, 3H), 2.87-3.01 (m, 1H), 3.36-3.42 (m,1H), 4.28 (d, J=17.3 Hz, 1H), 4.36 (d, J=17.5 Hz, 1H), 4.53 (s, 2H),5.12-5.19 (dd, J=4.9, 13.1 Hz, 1H), 6.07 (d, J=7.7 Hz, 1H), 7.38 (d,J=7.4 Hz, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 11.03 (s,1H). ¹³C NMR (DMSO-d₆) δ: 22.69, 25.10, 25.35, 31.14, 33.22, 34.00,46.12, 48.21, 49.34, 51.45, 121.59, 128.30, 130.08, 131.87, 134.41,139.99, 157.09, 168.02, 170.99, 172.84. Anal Calcd forC₂₂H₂₈N₄O₄+0.1H₂O: C, 63.78; H, 6.86; N, 13.52. Found: C, 63.41; H,6.93; N, 13.33.

5.323-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

To a suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and 3-chloro-phenyl-isocyanate (0.27mL, 2.23 mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine(0.45 mL g, 2.60 mmol). The mixture was stirred at room temperatureovernight. The mixture was quenched with MeOH and filtered. Theresulting solid was rinsed with CH₂Cl₂ (5 mL) to give3-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea(0.68 g, 82%): mp 193-195° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=3.29 (99%); ¹H NMR(DMSO-d₆): δ 2.00-2.04 (m, 1H), 2.32-2.38 (m, 1H), 2.56-2.63 (m, 1H),2.85-2.92 (m, 1H), 2.98 (s, 3H), 4.38 (d, J=17.3 Hz, 1H), 4.45 (d,J=17.3 Hz, 1H), 4.65 (s, 2H), 5.10-5.18 (dd, J=4.5, 13.2 Hz, 1H), 7.00(d, J=7.8 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.46-7.41 (In, 2H), 7.53 (t,J=7.5 Hz, 1H), 7.64-7.67 (m, 2H), 8.65 (s, 1H), 11.13 (s, 1H). ¹³C NMR(DMSO-d₆) δ: 22.57, 31.19, 34.76, 46.27, 48.37, 51.60, 118.00, 119.08,121.42, 121.77, 128.48, 129.85, 129.92, 131.93, 132.69, 133.62, 140.15,142.04, 155.34, 168.00, 171.01, 172.84. Anal Calcd for C₂₂H₂₁ClN₄O₄: C,59.93; H, 4.80; N, 12.71, Cl, 8.04. Found: C, 59.30; H, 4.66; N, 12.33,Cl, 8.36.

5.331-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-1-methyl-urea

To a suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and 4-methoxy-phenyl-isocyanate (0.29mL, 2.23 mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine(0.45 mL g, 2.60 mmol). The mixture was stirred at room temperatureovernight. The mixture was quenched with MeOH and filtered. Theresulting solid was rinsed with CH₂Cl₂ (5 mL) to give1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-1-methyl-urea(0.38 g, 46%): mp 245-247° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=1.91 (98%); ¹H NMR(DMSO-d₆): δ 1.99-2.04 (m, 1H), 2.30-2.37 (m, 1H), 2.56-2.63 (m, 1H),2.85-2.87 (m, 1H), 2.95 (s, 3H), 3.70 (s, 3H), 4.37 (d, J=17.3 Hz, 1H),4.44 (d, J=17.4 Hz, 1H), 4.63 (s, 2H), 5.11-5.18 (dd, J=4.9, 13.1 Hz,1H), 6.84 (d, J=8.9 Hz, 2H), 7.32 (d, J=8.9 Hz, 2H), 7.45 (d, J=7.4 Hz,1H), 7.53 (t, J=7.4 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 8.31 (s, 1H), 11.02(s, 1H). ¹³C NMR (DMSO-d₆) δ: 22.58, 31.17, 34.64, 46.26, 48.36, 51.57,55. 10, 113.46, 121.69, 122.01, 128.41, 129.91, 131.91, 133.29, 133.98,140.13, 154.64, 155.91, 168.02, 171.02, 172.85. Anal Calcd forC₂₃H₂₄N₄O₅+0.1H₂O: C, 63.03; H, 5.57; N, 12.78. Found: C, 62.96; H,5.48; N, 12.49.

5.341-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-(3-trifluoromethyl-phenyl)-urea

To a suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and α,α,α-trifluoro-m-tolyl-isocyanate(0.29 mL, 2.23 mmol) in dry CH₂Cl₂ (80 ml), was addeddiisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred atroom temperature overnight. The mixture was quenched with MeOH andfiltered. The resulting solid was rinsed with CH₂Cl₂ (5 mL) to give1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-(3-trifluoromethyl-phenyl)-urea(0.58 g, 66%): mp 198-200° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=1.91 (98%); ¹H NMR(DMSO-d₆): δ 2.00-2.05 (m, 1H), 2.28-2.39 (m, 1H), 2.56-2.63 (m, 1H),2.85-2.93 (m, 1H), 3.01 (s, 3H), 4.32-4.53 (dd, J=8, 20 Hz, 2H), 4.67(s, 2H), 5.11-5.18 (dd, J=5.9, 15.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H),7.44-7.57 (m, 3H), 7.65 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.94(s, 1H), 8.81 (s, 1H), 11.02 (s, 1H). ¹³C NMR (DMSO-d₆) δ: 22.56, 31.17,34.76, 46.25, 48.36, 51.60, 115.71, 118.50, 121.78, 123.15, 126.42,128.49, 128.83, 129.44, 129.81, 131.94, 133.59, 140.14, 141.33, 155.41,168.00, 171.01, 172.82. Anal Calcd for C₂₃H₂₁F₃N₄O₄: C, 58.23; H, 4.46;N, 11.81, F, 12.01. Found: C, 58.06; H, 4.30; N, 12.09, F, 11.59.

5.353-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

To a suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.65 g, 1.93 mmol) and 3-chloro-isocyanate (0.28 mL, 2.31mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine (0.47 mL g,2.60 mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was added water (40 mL) and 1N HCl (40 mL). The mixturewas extracted, and the organic layer was washed with brine (40 mL) andconcentrated on rota-vap. The resulting oil was purified on silica gelcolumn to give3-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-ureaas a solid (0.55 g, 62%)): mp 193-195° C.; HPLC: Waters Symmetry C-18,3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=6.23(99%); ¹H NMR (DMSO-d₆): δ 2.05-2.09 (m, 1H), 2.58-2.64 (m, 1H),2.84-2.91 (m, 1H), 3.05 (s, 3H), 5.01 (s, 2H), 5.14-5.21 (dd, J=5.2,12.5 Hz, 1H, 7.00 (d, J=7.9 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.43 (d,J=8.2 Hz, 1H), 7.62 (d, J=6.9 Hz, 1H), 7.70 (s, 1H), 7.90-7.81 (m, 2H),8.70 (s, 1H), 11.15 (s, 1H). ¹³C NMR (DMSO-d₆) δ: 21.99, 30.94, 35.19,47.54, 48.87, 117.99, 119.08, 121.46, 121.95, 127.60, 129.89, 131.83,132.42, 132.67, 135.05, 138.50, 141.99, 155.45, 166.97, 167.59, 169.84,172.78. Anal Calcd for C₂₂H₁₉ClN₄O₅: C, 58.09; H, 4.21; N, 12.32. Found:C, 58.01; H, 4.40; N, 12.00.

5.363-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

To a suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.65 g, 1.93 mmol) and t-butyl-isocyanate (0.26 mL, 2.31mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine (0.47 mL g,2.60 mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was added water (40 mL) and 1N HCl (40 mL). The mixturewas quenched with MeOH and extracted with H₂O (40 mL), then with 1N HCl(40 mL). The organic layer was washed with brine (40 mL) andconcentrated on rota-vap. The resulting oil was purified on silica gelcolumn to give3-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea(0.59 g, 76%): mp 188-190° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=3.14 (96%); ¹H NMR(DMSO-d₆): δ 1.28 (s, 9H), 2.08 (m, 1H), 2.64-2.50 (m, 2H), 2.85 (s,3H), 2.87-2.95 (m, 1H), 4.87 (s, 2H), 5.14-5.18 (dd, J=5.3, 12.6 Hz,1H), 5.71 (s, 1H), 7.50-7.52 (m, 1H), 7.79-7.88 (m, 2H), 11.13 (s, 1H).¹³C NMR (DMSO-d₆) δ: 21.95, 29.13, 30.90, 34.81, 47.02, 48.82, 50.07,121.70, 127.45, 131.73, 132.49, 134.78, 139.63, 157.40, 166.95, 167.61,169.80, 172.73. Anal Calcd for C₂₀H₂₄N₄O₅: C, 59.99; H, 6.04; N, 13.99.Found: C, 59.87; H, 6.01; N, 13.83.

5.373-(3,5-dichloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

To a suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and 3,5-dichlorophenyl-isocyanate(0.42 g, 2.23 mmol) in dry CH₂Cl₂ (80 ml), was addeddiisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred atroom temperature overnight. The mixture was quenched with MeOH andfiltered. The resulting solid was rinsed with CH₂Cl₂ (5 mL) to give3-(3,5-dichloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea(0.76 g, 86%): mp 285-287° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=6.97 (99%); ¹H NMR(DMSO-d₆): δ 2.00-2.05 (m, 1H), 2.33-2.40 (m, 1H), 2.57-2.64 (m, 1H),2.85-2.94 (m, 1H), 2.98 (s, 3H), 4.37 (d, J=17.3 Hz, 1H), 4.45 (d, J=7.4Hz, 1H), 4.65 (s, 2H), 5.10-5.18 (dd, J=4.9, 13.1 Hz, 1H), 7.13 (s, 1H),7.45 (d, J=8.9 Hz, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.63-7.67 (m, 3H), 8.80(s, 1H), 11.01 (s, 1H). ¹³C NMR (DMSO-d₆) δ: 22.57, 31.19, 34.78, 46.26,48.37, 51.61, 117.44, 120.77, 121.82, 128.51, 129.81, 131.95, 133.40,133.65, 140.15, 143.05, 155.03, 167.98, 171.00, 172.83. Anal Calcd forC₂₂H₂₀Cl₂N₄O₄+0.2 CH₂Cl₂: C, 54.16; H, 4.18; N, 11.38, Cl, 17.28. Found:C, 54.34; H, 3.95; N, 11.29, Cl, 17.13.

5.381-[2-(2,6-dioxo-piperidin-3-yl)-1-OXO-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(3-fluoro-phenyl)-1-methyl-urea

Diisopropylethylamine (0.3 g, 2.6 mmol) was added to a stirredsuspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.6 g, 1.9 mmol) and 3-fluorophenyl isocyanate (0.3 g,2.2 mmol) in dry methylene chloride (80 mL). The resulting mixture wasstirred at room temperature overnight. Solid was collected to give 0.7 g(84%) of product: mp 218-220° C.; ¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 8.66(s, 1H), 7.67 (d, J=6.0 Hz, 1H), 7.56-7.22 (m, 5H), 6.79-6.72 (m, 1H),5.17-5.11 (dd, J=6.0 and 12.0 Hz, 1H), 4.66 (s. 2H), 4.46 (d, J=15 Hz,1H), 4.38 (d, J=18 Hz, 1H), 2.99 (s, 3H), 2.97-2.86 (m, 1H), 2.63-2.57(m, 1H), 2.38-2.33 (m, 1H), 2.09-2.02 (m, 1H); ¹³C NMR (DMSO-d₆) δ172.80, 170.97, 167.97, 163.68 (160.50), 155.33, 142.44 (142.30),140.14, 133.61, 131.90, 129.79, 129.66, 128.44, 121.73, 115.23, 108.21(107.93), 106.38 (106.03), 51.58, 48.32, 46.25, 34.75, 31.15, 22.53;Anal. Calcd. For C₂₂H₂₁FN₄O₄: C, 62.26; H, 4.99; N, 13.20; F, 4.48.Found: C, 62.09; H, 4.92; N, 13.05; F, 4.41.

5.393-(3,5-difluoro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Diisopropylethylamine (0.3 g, 2.6 mmol) was added to a stirredsuspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.6 g, 1.9 mmol) and 3,5-difluorophenyl isocyanate (0.4g, 2.2 mmol) in dry methylene chloride (80 mL). The resulting mixturewas stirred at room temperature overnight. Solid was collected to give0.6 g (76%) of product: mp 228-230° C.; ¹H NMR (DMSO-d₆) δ 11.01 (s,1H), 8.84 (s, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.45(d, J=7.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 2H), 6.75 (t, J=9.3 Hz, 1H),5.17-5.10 (dd, J=4.9 and 13.1 Hz, 1H), 4.65 (s, 2H), 4.45 (d, J=17.4 Hz,1H), 4.38 (d, J=17.3 Hz, 1H), 2.99 (s, 3H), 2.92-2.85 (m, 1H), 2.63-2.57(m, 1H), 2.45-2.30 (m, 1H), 2.04-2.00 (m, 1H); ¹³CNMR (DMSO-d₆) δ172.84, 171.01, 167.99, 164.35 (164.10), 160.51 (160.26), 155.07, 143.32(143.55, 143.09), 140.17, 133.43, 131.94, 129.80, 128.50, 121.81, 102.17(102.00), 101.88 (101.71), 96.61 (97.03, 96.19), 51.62, 48.33, 46.27,34.80, 31.18, 22.55; Anal. Calcd. for C₂₂H₂₀F₂N₄O₄: C, 59.73; H, 4.56;N, 12.66; F, 8.59. Found: C, 59.59; H, 4.71; N, 12.46; F, 8.61.

5.403-(3,4-dimethyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

To a suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.65 g, 1.93 mmol) and 3,4-dimethylphenyl isocyanate(0.32 mL, 2.31 mmol) in dry CH₂Cl₂ (80 ml), was addeddiidopropylethylamine (0.47 mL g, 2.60 mmol). The mixture was stirred atroom temperature overnight. The reaction mixture was quenched with MeOH(1 mL). The suspension was filtered, and the resulting solid cake wasrinsed with CH₂Cl₂ (5 ml). The solid was reslurried with ether (I 5 mL)to give3-(3,4-dimethyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-ureaas a solid (0.51 g, 59%)): mp 202-204° C.; HPLC: Waters Symmetry C-18,3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=6.23(99%); ¹H NMR (DMSO-d₆): δ 2.14 (s, 3H), 2.16 (s, 3H), 2.54-2.64 (m,2H), 2.85-2.97 (m, 1H), 3.03 (s, 3H), 5.00 (s, 2H), 5.14-5.20 (dd,J=5.3, 12.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H),7.26 (s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.89-7.81 (m, 2H), 8.34 (s, 1H),11.15 (s, 1H). ¹³C NMR (DMSO-d₆) δ: 18.62, 15.54, 21.97, 30.91, 35.10,47.46, 48.85, 117.61, 121.43, 121.83, 127.54, 129.12, 129.51, 131.78,132.42, 134.95, 135.63, 137.93, 138.97, 155.79, 16696, 167.58, 169.80,172.74. Anal Calcd for C₂₄H₂₄N₄O₅: C, 64.28; H, 5.39; N, 12.49. Found:C, 63.99; H, 5.26; N, 12.39.

5.411-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-naphthalen-1-yl-urea

To a suspension of3-(4-methylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and 1-naphthyl isocyanate (0.32 mL,2.23 mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine (0.45mL g, 2.60 mmol). The mixture was stirred at room temperature overnight.The mixture was quenched with MeOH and filtered. The resulting solid wasrinsed with CH₂Cl₂ (5 mL) to give1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-naphthalen-1-yl-urea(0.76 g, 89%): mp 292-294° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, 40/60 (CH₃CN/H₂O): t_(R)=2.65 (99%); ¹H NMR(DMSO-d₆): δ 2.00-2.05 (m, 1H), 2.29-2.35 (m, 1H), 2.56-2.62 (m, 1H),2.87-2.97 (m, 1H), 3.09 (s, 3H), 4.40 (d, J=17.3 Hz, 1H), 4.47 (d,J=17.4 Hz, 1H), 4.72 (s, 2H), 5.13-5.19 (dd, J=5.1, 13.3 Hz, 1H),7.47-7.93 (m, 10H), 8.57 (s, 1H), 11.04 (s, 1H). ¹³C NMR (DMSO-d₆) δ:22.62, 31.14, 34.78, 46.20, 48.55, 51.52, 121.70, 123.30, 123.38,125.46, 125.48, 125.74, 127.87, 128.42, 129.63, 129.91, 131.95, 133.71,133.99, 135.39, 140.17, 156.71, 168.02, 170.99, 172.81. Anal Calcd forC₂₆H₂₄N₄O₄: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.54; H, 5.12; N,11.87.

5.423-(3-chloro-4-methyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Diisopropylethylamine (0.4 g, 2.6 mmol) was added to a stirredsuspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and 3-chloro-4-methyl-henyl isocyanate(0.4 g, 2.3 mmol) in dry CH₂Cl₂ (80 mL). Reaction mixture was stirred atroom temperature overnight. Reaction mixture was filtered, and solid wasslurried in acetone (15 mL) to give 0.7 g (80%) of product: mp 193-195°C.; ¹H NMR (DMSO-d₆) δ 11.15 (s, 1H), 8.59 (s, 1H), 7.87-7.84 (m, 2H),7.68-7.60 (m, 2H), 7.37-7.34 (dd, J=2. 1 and 8.3 Hz, 1H), 7.21 (d, J=8.5Hz, 1H), 5.20-5.14 (dd, J=5.6 and 12.3 Hz, 1H), 5.01 (s, 2H), 3.04 (s,3H), 2.92 (m, 1HO, 2.58 (m, 2H), 2.24 (s, 3H), 2.08 (m, 1H); ¹³C NMR(DMSO-d₆) δ 172.74, 169.80, 167.56, 166.94, 155.51, 139.57, 138.64,135.00, 132.58, 132.42, 131.79, 130.64, 128.21, 127.56, 121.89, 119.68,118.39, 48.85, 47.49, 35.11, 30.91, 21.97, 18.74; Anal. Calcd. forC₂₃H₂₁ClN₄O₅: C, 58.92; H, 4.51; N, 11.95; Cl, 7.56. Found: C, 58.81; H,4.29; N, 11.74; Cl, 7.79.

5.433-(4-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Diisopropylethylamine (0.4 g, 2.6 mmol) was added to a stirredsuspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 10.9 mmol) and 4-chlorophenyl isocyanate (0.4 g,2.3 mmol) in dry CH₂Cl₂ (80 mL). Reaction mixture was stirred at roomtemperature overnight. Reaction mixture was filtered, and solid wasslurried in acetone (15 mL) to give 0.7 g (80%) of product: mp 279-281°C.; ¹H NMR (DMSO-d₆) δ 11.15 (s, 1H), 8.64 (s, 1H), 7.86-7.83 (m, 2H),7.63 (d, J=1.4 Hz, 1H), 7.55-7.52 (dd, J=2.1 and 6.8 Hz, 2H), 7.30-7.27(dd, J=2.1 and 6.9 Hz, 2H), 5.20-5.14 (dd, J=6.6 and 13.2 Hz, 1H), 5.01(s, 2H), 3.05 (s, 3H), 2.97-2.85 (m, 1H), 2.65-2.57 (m, 2H0, 2.11-2.02(m, 1H); ¹³C NMR (DMSO-d₆) δ 172.68, 169.74, 167.50, 166.88, 155.50,139.30, 138.57, 134.93, 132.36, 131.73, 128.00, 127.51, 125.42, 121.83,121.28, 48.78, 47.42, 35.08, 30.84, 21.90; Anal. Calcd. forC₂₂H₁₉ClN₄O₅: C, 58.09; H, 4.21; N, 12.32; Cl, 7.79. Found: C, 57.79; H,4.05; N, 12.05; Cl, 7.84.

5.441-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-naphthalen-2-yl-urea

Diisopropylethylamine (0.3 g, 2.6 mmol) was added to a stirredsuspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.6 g, 1.9 mmol) and 2-naphthyl isocyanate (0.4 g, 2.2mmol) in dry methylene chloride (80 mL). The resulting mixture wasstirred at room temperature overnight. Solid was collected and slurriedwith acetone (20 mL) to give 0.7 g (81%) of product: mp 292-294° C.; ¹HNMR (DMSO-d₆) δ 11.02 (s, 1H), 8.69 (s, 1H), 8.03 (d, J=1.8 Hz, 1H),7.81-7.32 (m, 9H), 5.17-5.11 (dd, J=5.1 and 13.2 Hz, 1H), 4.70 (s, 2H),4.48 (d, J=17.3 Hz, 1H), 4.41 (d, J=17.3 Hz, 1H), 3.04 (s, 3H),2.97-2.85 (m, 1H), 2.60-2.54 (m, 1H), 2.38-2.32 (m, 1H), 2.04-1.99 (m,1H); ¹³C NMR (DMSO-d₆) δ 172.79, 170.98, 168.00, 155.70, 140.15, 138.10,133.80, 133.44, 131.92, 129.86, 129.13, 128.44, 127.69, 127.31, 126.89,126.09, 123.94, 121.71, 121.29, 115.31, 51.59, 48, 41, 46.29, 34.80,31.13, 22.54; Anal. Calcd. for C₂₆H₂₄N₄O₄: C, 68.41; H, 5.30; N, 12.27.Found: C, 68.32; H, 5.28; N, 12.11.

5.45(2-{[2-(2,6-dioxo-piperidin-3-yl)-1-OXO-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamoyl}-ethyl)-carbamicacid tert-butylester

1,8-Diazabicyclo[5,4,0]undec-7-ene (2.4 g, 15.5 mmol) was added to astirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (2.0 g, 6.2 mmol) in dry CH₃CN (80 mL). After stirring for5 minutes, 1-hydroxybenzotriazole (1.0 g, 7.4 mmol) and N-BOC-β-alanine(1.3 g, 6.8 mmol) were added, followed by1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.8 g, 9.3mmol). The resulting mixture was stirred at room temperature overnight.Reaction mixture was concentrated, and residue was dissolved inmethylene chloride (80 mL), washed with H₂O (2×40 mL) and brine (40 mL),and dried (MgSO₄). Solvent was removed, and residue was purified bychromatography (CH₃OH: CH₂Cl₂ 3:97) to give 2.2 g (76%) of product: mp222-224° C.; ¹H NMR (DMSO-d₆) δ 11.0 (s, 1H), 7.68-7.28 (m, 3H), 6.74(t, J=5.3 Hz, 1H), 5.15-5.09 (dd, J=5.3 and 13.2 Hz, 1H), 4.69-4.28 (m,4H), 3.19-3.15 (m, 2H), 2.96 (s, 3H), 2.93-2.83 (m, 1H), 2.64-2.36 (m,2H), 2.08-2.00 (m, 1H), 1.37 (s, 9H); ¹³C NMR (DMSO-d₆) δ 172.82,171.06, 170.96, 167.96, 155.45, 140.27, 133.00, 131.85, 130.18, 128.33,121.73, 77.57, 51.59, 46.76, 46.29, 36.40, 35.05, 32.78, 31.16, 28.19,22.51; Anal. Calcd. for C₂₃H₃₀N₄O₆+0.8H₂O: C, 58.41; H, 6.73; N, 11.85.Found: C, 58.12, H, 6.84; N, 11.66.

5.463-benzyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

To a suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.60 g, 1.86 mmol) and benzyl isocyanate (0.28 mL, 2.23mmol) in dry CH₂Cl₂ (80 ml), was added diisopropylethylamine (0.45 mL g,2.60 mmol). The mixture was stirred at room temperature overnight. Themixture was quenched with MeOH, and water (40 mL) and 1N HCl (40 mL)were added. The mixture was extracted, and the organic layer was washedwith brine (40 mL) and concentrated on rota-vap. The resulting oil waspurified on silica gel column to give1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-naphthalen-2-yl-urea(0.49 g, 62%): mp 216-218° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5micro, mL/min, 240 nm, 30/70 (CH₃CN/H₂O): t_(R)=3.48 (99%); ¹H NMR(DMSO-d₆): δ 1.96-2.00 (m, 1H), 2.21-2.72 (m, 1H), 2.56-2.62 (m, 1H),2.85 (s, 3H), 2.87-2.91 (m, 1H), 4.23-4.28 (m, 3H), 4.36 (d, J=17.4 Hz,1H), 4.57 (s, 2H), 5.08-5.14 (dd, J 5.1, 13.3 Hz, 1H), 7.08 (t, J=5.9Hz, 1H), 7.17-7.32 (m, 5H), 7.39 (d, J=7.2 Hz, 1H), 7.51 (t, J=7.5 Hz,1H), 7.08 (d, J=7.0 Hz, 1H), 11.02 (s, 1H). ¹³C NMR (DMSO-d₆) δ: 22.50,31.18, 34.11, 43.59, 46.14, 48.25, 51.50, 121.58, 126.36, 126.90,128.04, 128.29, 129.86, 131.86, 134.18, 140.05, 141.08, 157.84, 168.01,170.92, 172.82. Anal Calcd for C₂₃H₂₄N₄O₅: C, 65.70; H, 5.75; N, 13.32.Found: C, 65.54; H, 5.67; N, 13.15.

5.47N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-methoxy-N-methyl-benzamide

Triethylamine (0.5 g, 4.8 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and m-anisoyl chloride (0.5 g, 2.7 mmol)in THF (30 mL). Reaction mixture was stirred at room temperatureovernight. Reaction mixture was quenched with methanol (1 mL) andconcentrated. Residue was dissolved in methylene chloride (70 mL) andwashed with 1N HCL (30 mL), H₂O (30 mL) and brine (30 mL), and dried(MgSO₄). Solvent was removed, and residue was purified by chromatography(SiO₂, EtOAc: CH₂Cl₂ 40:60) to give 0.6 g (71%) of product: mp 216-218°C.; ¹H NMR (DMSO-d₆) δ 11.13 (s, 1H), 7.91-7.76 (m, 3H), 7.39-7.28 (m,1H), 7.06-6.92 (m, 3H), 5.12-4.92 (m, 3H), 3.80 (s, 3H), 2.96 (s, 3H),2.96-2.85 (m, 1H), 2.63-2.51 (m, 2H), 2.08-1.99 (m, 1H); ¹³CNMR(DMSO-d₆) δ 172.73, 169.77, 166.87, 159.03, 137.30, 135.17, 132.77,131.86, 129.63, 127.77, 122.14, 119.01, 118.18, 115.22, 112.39, 111.71,55.23, 48.87, 46.00, 37.72, 30.90, 21.94; Anal. Calcd. for C₂₃H₂₁N₃O₆:C, 63.44; H, 4.86; N, 9.65. Found: C, 63.50; H, 4.99; N, 9.52.

5.48 furan-2-carboxylic acid[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-H-isoindol-4-ylmethyl]-methyl-amide

Triethylamine (0.5 g, 4.8 mmol) was added to a stirred suspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and 2-furoyl chloride (0.4 g, 2.7 mmol)in THF (30 mL). Reaction mixture was stirred at room temperatureovernight. Reaction mixture was quenched with methanol (1 mL) andconcentrated. Residue was dissolved in methylene chloride (70 mL) andwashed with 1N HCl (30 mL), H₂O (30 mL), and brine (30 mL), and dried(MgSO₄). Solvent was removed, and residue was purified by chromatography(SiO₂, EtOAc: CH₂Cl₂ 40:60) to give 0.6 g (73%) of product: mp 184-186°C.; ¹H NMR (DMSO-d₆) δ 11.15 (s, 1H), 7.89-7.84 (m, 3H), 7.65-7.61 (m,1H), 7.14 (b, 1H), 6.64 (b, 1H), 5.20-5.23 (m, 3H), 3.36 (b, 3H),2.98-2.83 (m, 1H), 2.64-2.53 (m, 2H), 2.11-2.05 (m, 1H); ¹³C NMR(DMSO-d₆) δ 172.72, 169.79, 167.47, 166.88, 159.74, 146.10, 145.14,137.41, 135.09, 132.40, 131.85, 127.64, 122.11, 116.31, 111.44, 48.88,30.90, 21.95; Anal. Calcd. for C₂₀H₁₇N₃O₆: C, 60.76; H, 4.33; N, 10.63.Found: C, 60.44; H, 4.24; N, 10.33.

5.491-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-naphthalen-1-yl-urea

1-Naphthyl isocyanate (0.4 g, 2.2 mmol) was added to a stirredsuspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and triethylamine (0.3 g, 2.7 mmol) inTHF (40 mL). Reaction mixture was stirred at room temperature overnight.Reaction mixture was concentrated, and residue was stirred with 1N HCl(20 mL). Solid was collected and slurried in acetone (15 mL) to give 0.8g of crude product. Crude product was purified by preparatorychromatography to give 0.3 g (53%) of product: mp 272-274° C.; ¹H NMR(DMSO-d₆) δ 11.15 (s, 1H), 8.66 (s, 1H), 7.93-7.48 (m, 10H), 5.14-5.09(m, 3H), 3.16 (s, 3H), 2.91-2.86 (m, 1H), 2.64-2.50 (m, 2H), 2.07 (m,1H); ¹³C NMR (DMSO-d₆) δ 172.75, 169.81, 167.57, 167.00, 156.88, 139.02,135.34, 134.99, 133.71, 132.39, 131.85, 129.57, 127.86, 127.66, 125.73,125.46, 125.04, 123.49, 123.27, 121.87, 48.86, 47.70, 34.00, 30.92,21.99; Anal. Calcd. for C₂₆H₂₂N₄O₅+0.15H₂O: C, 66.00; H, 4.75; N, 11.84.Found: C, 65.62; H, 4.50; N, 11.70.

5.503,4-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-N-methyl-benzamide

Triethylamine (0.5 g, 4.7 mmol) was added to a stirred suspension of3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride (0.6 g, 1.9 mmol) and 3,4-dichlorobenzoyl chloride (0.6 g,2.6 mmol) in THF (30 mL). Reaction mixture was stirred at roomtemperature overnight. Reaction mixture was quenched with methanol (1mL) and concentrated. Residue was dissolved in methylene chloride (70mL) and washed with 1N HCl (30 mL), H₂O (30 mL), and brine (30 mL), anddried (MgSO₄). Solvent was removed, and residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 5:95) to give 0.7 g (70%) ofproduct: mp 228-230° C.; ¹H NMR (DMSO-d₆) δ 11.02 (s, 1H), 7.81-7.42 (m,6H), 5.17-5.13 (m, 1H), 4.76-4.22 (m, 4H), 2.97 (s, 3H), 2.97-2.89 (m,1H), 2.64-2.57 (m, 1H), 2.42-2.36 (m, 1H), 2.08-2.01 (m, 1H); ¹³CNMR(DMSO-d₆) δ 172.83, 170.96, 167.95, 136.53, 132.28, 132.15, 131.98,131.34, 130.75, 130.57, 129.08, 128.54, 127.26, 126.70, 122.03, 51.59,47.05, 46.31, 37.18, 31.17, 22.55; Anal. Calcd. for C₂₂H₁₉Cl₂N₃O₄: C,57.40; H, 4.16; N, 9.13; Cl, 15.40. Found: C, 57.11, H, 4.13,N, 8.95,Cl, 15.45.

5.513-(3,4-dichloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

Diisopropylethylamine (0.4 g, 2.7 mmol) was added to a stirredsuspension of2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dionehydrochloride (0.7 g, 1.9 mmol) and 3,4-dichlorophenyl isocyanate (0.4g, 2.3 mmol) in dry CH₂Cl₂ (80 mL). Reaction mixture was stirred at roomtemperature overnight. Reaction mixture was filtered and solid wasslurried in ether (15 mL) to give 0.8 g (89%) of product: mp 255-257°C.; ¹H NMR (DMSO-d₆) δ 11.16 (s, 1H), 8.81 (s, 1H), 7.89-7.82 (m, 3H),7.63-7.60 (m, 1H), 7.54-7.46 (m, 2H), 5.21-5.14 (dd, J=5.2 and 12.4 Hz,1H), 5.01 (s, 2H), 3.05 (s, 3H), 2.91-2.84 (m, 1H), 2.64-2.49 (m, 2H),2.09-2.05 (m, 1H); ¹³CNMR (DMSO-d₆) δ 172.78, 169.84, 167.58, 166.96,155.31, 140.71, 138.42, 135.07, 132.43, 131.83, 130.51, 130.11, 127.59,123.13, 121.97, 120.70, 119.58, 48.87, 47.56, 35.19, 30.94, 21.99; Anal.Calcd. For C₂₂H₁₈Cl₂N₄O₅: C, 54.00; H, 3.71; N, 11.45; Cl, 14.49. Found:C, 53.84; H, 3.56; N, 11.27; Cl, 14.61.

5.52 Assays 5.52.1 TNFα Inhibition Assay in PMBC

Peripheral blood mononuclear cells (PBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPMI 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mlpenicillin, and 100 μg/ml streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat. no. L-1887, St.Louis, Mo., USA) at 1 ng/ml final in the absence or presence ofcompounds. Compounds of the invention are dissolved in DMSO (Sigma) andfurther dilutions are done in culture medium immediately before use. Thefinal DMSO concentration in all assays can be about 0.25%. Compounds areadded to cells 1 hour before LPS stimulation. Cells are then incubatedfor 18-20 hours at 37° C. in 5% CO₂, and supernatants are thencollected, diluted with culture medium and assayed for TNFα levels byELISA (Endogen, Boston, Mass., USA). IC₅₀s are calculated usingnon-linear regression, sigmoidal dose-response, constraining the top to100% and bottom to 0%, allowing variable slope (GraphPad Prism v3.02).

5.52.2 IL=2 and MIP-3α Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mlcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×10⁸ non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μlanti-CD16, 15 μl anti-CD33, 15 μl anti-CD56, 0.23 ml anti-CD19 beads,0.23 ml anti-HLA class II beads, and 56 μl anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3⁺ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/ml in PBS, 100 μl per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μl/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds of the invention is diluted 1:50 in complete for the first 20×dilution of 200 μM in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3α by ELISA (R&DSystems). IL-2 and MIP-3α levels are normalized to the amount producedin the presence of an amount of a compound of the invention, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

5.52.3 Cell Proliferation Assay

Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig,Germany). The cell line KG-1 is obtained from the American Type CultureCollection (Manassas, Va., USA). Cell proliferation as indicated by³H-thymidine incorporation is measured in all cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μl/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

5.52.4 Immunoprecipitation and Immunoblot

Namalwa cells are treated with DMSO or an amount of a compound of theinvention for 1 hour, then stimulated with 10 U/ml of Epo (R&D Systems)for 30 minutes. Cell lysates are prepared and either immunoprecipitatedwith Epo receptor Ab or separated immediately by SDS-PAGE. Immunoblotsare probed with Akt, phospho-Akt (Ser473 or Thr3O₈), phospho-Gab1(Y627), Gab1, IRS2, actin and IRF-1 Abs and analyzed on a Storm 860linager using ImageQuant software (Molecular Dynamics).

5.52.5 Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound of the inventionovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

5.52.6 Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound of the inventionat various tine points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

5.52.7 Luciferase Assay

Namalwa cells are transfected with 4 μg of AP1-luciferase (Stratagene)per 1×10⁶ cells and 3 μl Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound of the invention.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or willbe able to ascertain using no more than routine experimentation,numerous equivalents of specific compounds, materials, and procedures.All such equivalents are considered to be within the scope of theinvention and are encompassed by the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art to this invention. Thefull scope of the invention is better understood with reference to theappended claims.

1. A compound of formula (I):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: *denotes chiral center; X is CH₂ or C═O; R¹ is H, (C₁-C₈)alkyl,(C₃-C₇)cycloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, benzyl, aryl,(C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl, (C₀-C₄)alkyl-(C₂-C₅)heteroaryl,C(O)R³, C(S)R³, C(O)OR⁴, (C₁-C₈)alkyl-N(R⁶)₂, (C₁-C₈)alkyl-OR⁵,(C₁-C₈)alkyl-C(O)OR⁵, C(O)NHR³, C(S)NH R³, C(O)NR³R^(3′), C(S)NR³R^(3′)or (C₁-C₈)alkyl-O(CO)R⁵; R² is H, CH₃, or (C₂-C₈)alkyl; R³ and R^(3′)are independently (C₁-C₈)alkyl; (C₃-C₇)cycloalkyl; (C₂-C₈)alkenyl;(C₂-C₈)alkynyl; benzyl; (C₀-C₄)alkyl-(C₅-C₁₀)aryl, optionallysubstituted with one or m-ore of: (C₁-C₆)alkyl, said alkyl itselfoptionally substituted with one or more halogen, (C₁-C₆)alkoxy, saidalkoxy itself optionally substituted with one or more halogen, SCY₃,wherein Y is hydrogen or halogen, NZ₂, wherein Z is hydrogen or(C₁-C₆)alkyl (C₁-C₆)alkylenedioxy, or halogen;(C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl; (C₀-C₄)alkyl-(C₂-C₈)heteroaryl;(C₀-C₈)alkyl-N(R⁶)₂; (C₁-C₈)alkyl-OR⁵; (C₁-C₈)alkyl-C(O)OR⁵;(C₁-C₈)alkyl-O(CO)R⁵; or C(O)OR⁵; R⁴ is (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₄)alkyl-OR⁵, benzyl, aryl,(C₀-C₄)alkyl-(C₁-C₆)heterocycloalkyl, or (C₀-C₄)alkyl-(C₂-C₉)heteroaryl;R⁵ is (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, benzyl,(C₅-C₁₀)aryl, or (C₂-C₉)heteroaryl; each occurrence of R⁶ isindependently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, benzyl,(C₅-C₁₀)aryl, (C₂-C₉)heteroaryl, or (C₀-C₈)alkyl-C(O)O—R⁵, or two R⁶groups can join to form a heterocycloalkyl group.
 2. The compound ofclaim 1 having a structure of formula (II):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: denotes chiral center; X is CH₂ or C═O; R is (C₁-C₆)alkyl;(C₁-C₆)alkoxy; amino; (C₁-C₆)alkyl-amino; dialkylamino, wherein each ofthe alkyl groups is independently (C₁-C₆)alkyl;(C₀-C₄)alkyl-(C₆-C₁₀)aryl, optionally substituted with one or more(C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen; 5 to 10 membered heteroaryl,optionally substituted with one or more (C₁-C₆)alkyl; —NHR′; or(C₀-C₈)alkyl-N(R′)₂; R¹ is: (C₁-C₆)alkyl; (C₀-C₄)alkyl-(C₆-C₁₀)aryl,optionally substituted with one or more of: (C₁-C₆)alkyl, said alkylitself optionally substituted with one or more halogen, (C₁-C₆)alkoxy,said alkoxy itself optionally substituted with one or more halogen,(C₁-C₆)alkylenedioxy, or halogen; or 5 to 10 membered heteroaryl,optionally substituted with one or more (C₁-C₆)alkyl; and eachoccurrence of R″ is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, benzyl, (C₆-C₁₀)aryl, 5 to 10 membered heteroaryl, or(C₀-C₈)alkyl-C(O)O—(C₁-C₈)alkyl.
 3. The compound of claim 2, wherein Xis C═O.
 4. The compound of claim 2, wherein R is methyl or ethyl.
 5. Thecompound of claim 2, wherein R is NHR′, and wherein R¹ is (C₆-C₁₀)aryl,optionally substituted with one or more (C₁-C₆)alkyl or (C₁-C₆)alkoxy.6. The compound of claim 5, wherein said alkyl or alkoxy is substitutedwith one or more of halogen.
 7. The compound of claim 2, wherein R is a5 to 10 membered heteroaryl.
 8. The compound of claim 2, wherein X isCH₂.
 9. The compound of claim 8, wherein R is methyl or ethyl.
 10. Thecompound of claim 2, wherein R is NHR′, and wherein R′ is (C₆-C₁₀)aryl,optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy, orhalogen.
 11. The compound of claim 10, wherein R¹ is phenyl, optionallysubstituted with one or more methyl, methoxy, trifluoromethyl, orchloride.
 12. The compound of claim 2, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein the compound is:


13. A pharmaceutical composition comprising a compound of claim
 1. 14. Amethod of treating, managing or preventing a disease or disorder whichcomprises administering to a patient in need of such treatment,management or prevention a therapeutically or prophylactically effectiveamount of a compound of claim 1, wherein the disease or disorder iscancer, a disorder associated with angiogenesis, pain, maculardegeneration or a related syndrome, a skin disease, a pulmonarydisorder, an asbestos-related disorder, a parasitic disease, animmunodeficiency disorder, a CNS disorder, CNS injury, atherosclerosisor a related disorder, dysfunctional sleep or a related disorder,hemoglobinopathy or a related disorder, or a TNFα related disorder. 15.The method of claim 14, wherein the disease is cancer.
 16. The methodsof claim 15, wherein the cancer is hematologic or solid cancer.
 17. Themethod of claim 14, which further comprises administration of one ormore additional active agents.
 18. The method of claim 14, wherein thecompound, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, is administered orally or parenterally.
 19. Asingle unit dosage form comprising a compound of claim
 1. 20. The singleunit dosage form of claim 19, which is suitable for oral or parenteraladministration.
 21. The single unit dosage form of claim 20, which issuitable for oral administration.
 22. The single unit dosage form ofclaim 21, which is a tablet or a capsule.